Skip to main content

Glucose metabolism and AD: evidence for a potential diabetes type 3

Abstract

Background

Alzheimer’s disease is the most prevalent cause of dementia in the elderly. Neuronal death and synaptic dysfunctions are considered the main hallmarks of this disease. The latter could be directly associated to an impaired metabolism. In particular, glucose metabolism impairment has demonstrated to be a key regulatory element in the onset and progression of AD, which is why nowadays AD is considered the type 3 diabetes.

Methods

We provide a thread regarding the influence of glucose metabolism in AD from three different perspectives: (i) as a regulator of the energy source, (ii) through several metabolic alterations, such as insulin resistance, that modify peripheral signaling pathways that influence activation of the immune system (e.g., insulin resistance, diabetes, etc.), and (iii) as modulators of various key post-translational modifications for protein aggregation, for example, influence on tau hyperphosphorylation and other important modifications, which determine its self-aggregating behavior and hence Alzheimer’s pathogenesis.

Conclusions

In this revision, we observed a 3 edge-action in which glucose metabolism impairment is acting in the progression of AD: as blockade of energy source (e.g., mitochondrial dysfunction), through metabolic dysregulation and post-translational modifications in key proteins, such as tau. Therefore, the latter would sustain the current hypothesis that AD is, in fact, the novel diabetes type 3.

Introduction

Alzheimer’s disease (AD) is the most common dementia with 60–70% of cases. Behavioral changes and cognitive impairment resulting from neurodegeneration are observed, possibly 10 years after the onset of proteinopathy. The two characteristic phenomena, used as biomarkers [1] are the presence of Ab plaques and hyperphosphorylation of tau that self-aggregates, forming neurofibrillary tangles (NFT) [2, 3]. However, AD is a multifactorial disease with a complex etiology. Two major groups of patients are evidenced: early-onset or familial with a hereditary component due to genetic mutations that alter the amyloid precursor protein (APP) or presenilins 1 and 2. The second group, late-onset or sporadic AD, occurs in 97% of cases. It is associated with multiple factors such as the polymorphism of apolipoprotein E (APOE) gene, presenting the APOε4 allele, hyperlipidemia, hypertension, type II diabetes, and coronary disease [4]. Age is one of the main associated risk factors for developing sporadic AD [5]. Different molecular events are involved. One of them is the misfolding of proteins due to the stress of the endoplasmic reticulum and failures in its quality control system of response to unfolded proteins (UPR) [6]. This enables for the accumulation of NFT.

Another alteration associated with age, due to the fact that neurons have a decreased capacity to regenerate, is the decrease in the amount of available energy [7]. This is due to two main reasons: the glucose transporters (GLUT) are expressed in less quantity [8] and alterations in insulin signaling [9].

The human brain uses 20% of the glucose [10]; it needs a lot of energy principally to support the synaptic activity [11]; 95% of glucose is used in the production of ATP [12]. This is why alterations in glucose metabolism cause damage to cell regulation, as decreased ATP can affect proper synaptic function [4]. Much of the process is independent of insulin regulation. However, there are insulin receptors in various brain areas, influencing processes such as memory, cognition, and regulation of energy metabolism [13, 14]. Insulin resistance significantly increases the risk of developing sporadic AD [15, 16], while type II diabetes (DTII) increases the risk of AD by 50% [17].

In addition, it has been shown that the development of insulin resistance and DTII may be mediated by endoplasmic reticulum (ER) stress by activating c-Jun N-terminal kinases (JNKs), and this in turn triggers downstream signaling cascade activity [18] of the inflammatory type [19], due to the excessively prolonged response to unfolded proteins (UPRs) by the stressed ER [19]. It has been shown that epigenetic variations such as glycosylations disturb protein folding and trigger ER stress [19]. All the latter also influence post-translational modifications in tau that propitiate tau self-assembly, from an a-helix to a b-sheet structure [20]. This b-sheet conformation is the one prone to form aggregates [20]. Increased phosphorylation, decreased ubiquitination, and decreased methylation are some of the post-translational changes observed in AD [21,22,23]. Remarkably, lysine methylation is decreased in AD patients [22], which may be explained by the decreased glucose uptake due to the downregulation of the GLUT receptors [24]. The latter is correlated with tau hyperphosphorylation [24], leading to the final outcome of neurodegeneration and neuroinflammation.

Here, we review how alterations in glucose metabolism stress the endoplasmic reticulum and this, in turn, influences the post-translational modifications of the tau protein associated with AD.

Metabolic alterations in the pathogenesis of AD

Endoplasmic reticulum (ER) stress

The cell has intracellular organelles that fulfill different functions, for example, in the nucleus the transcription of DNA to RNA [25]. In the ER, proteins are synthesized and subsequently transported to the Golgi apparatus, before their subsequent destination [26]. The ER has an intracellular membrane system, with a unique quality control system that allows the management of protein aggregates [27] and whose purpose is to maintain proteostasis [28].

ER stress is understood as the imbalance between ER protein folding capacity and the demand for protein synthesis, resulting in the accumulation of misfolded proteins in the ER lumen (misfolded) [29,30,31]. This can be produced by pathological conditions that can disrupt ER function, such as changes in the availability of Ca+2, ATP, or pathogens that release of misfolded or unfolded proteins (UPs) [32]. In the latter case, misfolded proteins or UP are directed towards a degradation pathway present in the ER called ERAD (ER-associated degradation) [33, 34]. UPs are recognized by chaperone proteins, which together with other proteins, stabilize unstable forms [35].

The ER is stressed when the amount of misfolded proteins exceeds its containment capacity, so mechanisms are displayed to correct this error [36]. A cellular UP response program (UPR) is activated to manage this error that acts through the reduction of the synthesis of new proteins and the transcription of chaperones and activates the degradation of UP in the proteasomes [27, 29, 37, 38].

Due to ER stress, sensors of the UP response are activated and decrease protein translation: IRE1 (endoribonuclease that requires inositol), PERK (protein kinase RNA-like endoplasmic reticulum kinase), and ATF6 (that activates transcription factor 6) [27, 32, 37, 39]. Then, the chaperone binding immunoglobulin protein (BiP) binds and inhibits one of the aforementioned transduction proteins, binding to misfolded proteins and adaptation to UP overload [32]. In this case, the UPR is not able to reestablish the folding equilibrium, and ER stress eventually leads to apoptosis [27, 40].

When the UPR is surpassed due to the excessive accumulation of misfolded proteins derived from environmental factors such as aging [31, 41], and genetic mutations, it could lead to diseases such as diabetes type 2 (DTII), atherosclerosis, and neurodegenerative diseases, e.g., AD, which is associated with abnormal protein folding [42].

Misfolded proteins that aggregate intracellularly constitute a hallmark in the pathogenesis of neurodegenerative diseases. It is likely that the ER regulatory mechanisms are bypassed, allowing self-aggregation and intracellular damage [41]. A tauopathy modeling was performed in a C-elegans; AD is one of them. The vital importance of IRE1 and ATF6, two of the UPR pathways to regulate proteostasis in ER, was highlighted [41]. Furthermore, a chronic UPR response can induce apoptosis through an intrinsic mitochondrial pathway dependent on members of the pro-apoptotic B cell lymphoma (Bcl-2) family [43]. If ER stress is prolonged, it causes an alteration in insulin synthesis, while apoptosis of B cell of the pancreas has been observed in the late stages of hyperglycemia and insulin resistance [44].

The large biosynthetic load on the ER for insulin production in response to glucose (from food intake) can exceed ER folding capacity, resulting in ER stress. This leads to the consequent activation of PERK, which reduces the ER protein load by phosphorylating eIF2 (elongation initiation factor-2), a protein necessary for protein translation [44]. It has been observed that in PERK −/− cells, protein synthesis does not respond to stress, leading to the accumulation of folded proteins (for example, proinsulin) and subsequently to apoptosis. In this case, ER stress-induced apoptosis can increase inflammatory signaling. PERK −/− mice are more prone to DTII and progressive hyperglycemia [45].

ER stress has also been related to diseases promoted by misfolded proteins or proteinopathies such as Alzheimer’s. There is an accumulation of misfolded proteins exceeding the response capacity of UPR [31]; greater markers of UPR activation have been demonstrated in the post-mortem brain of subjects with AD [38, 46]. It has been shown in transgenic animal models of AD that inhibition of PERK activity in hippocampal slices facilitates mGluR-LTD and, in turn, deletion of PERK deactivates the eIF2a pathway, which has been associated with improvements in memory [47]. UPR plays a fundamental role in the neurotoxicity manifested in AD [36]. Strong evidence shows that ER stress activates signaling pathways that influence tau phosphorylation, the amyloid cascade, and synaptic dysfunction [31].

Insulin resistance

Scientific evidence has proven that insulin signaling and glucose metabolism are altered in AD. For this reason, some authors such as Kroner [48] have designated AD as type III diabetes [16, 48].

Insulin is a polypeptide hormone made up of two chains of 51 long amino acids [49]; it is synthesized in B cells of the pancreas and regulates glucose metabolism [50], although it is also released locally in the CNS in minimal quantities [51]. It is synthesized as a prohormone, begins as a pre-proinsulin, and is eliminated in the rough ER cistern as proinsulin, and then it is directed to the Golgi apparatus, and it is packaged in secretory vesicles [52]. The proinsulin molecule dissociates as C peptide, by the enzymatic action of endopeptidases and carboxypeptidases, leaving the amino terminal peptide B linked by a disulfide bridge to the amino terminal peptide A. Then, its native structure is folded, and its conformation of two A chains and B is stabilized by the double disulfide bond [52, 53].

The peripheral areas of the body require insulin to activate the signaling that allows the translocation of glucose transporters, entering the glucose into the cell [54]. When insulin binds to the insulin receptor substrate or signaling adapter protein (IRS), it is recruited and phosphorylated [55]. The IRS activates downstream signaling pathways, of the IRS family; there are two fundamental ones: IRS1 and IRS 2. These activate two main signaling cascades such as the phosphatidylinositol 3-kinase (PI3K)-AKT/protein kinase B (PKB) pathway and mitogen-activated protein kinase (MAPK) pathways [54]. Furthermore, the expression of the activation of the PIK3 pathway together with glycosylation kinase (GSK-3) follows an expression similar to the insulin pathway in peripheral tissues [56]. The PIK3 pathway is considered an integrating pathway for insulin, and it is hypothesized that it is associated with learning and memory [50]. It was found in a group of diabetic women that they have greater cognitive impairment than women without diabetes [57]. Alterations in insulin signaling are associated with cognitive impairment [48].

In the CNS, insulin must cross the blood-brain barrier (BBB) and bind to its receptor, whose conformational change leads to the enzymatic activity of tyrosine kinase and the autophosphorylation of the receptor [58]. In the CNS, there are receptors in septum, amygdala, hypothalamus, hippocampus, cerebral cortex, and olfactory bulb [14, 59,60,61,62]. The function in the hypothalamus of the insulin receptor is through signaling of food intake and energy regulation, influencing peripheral metabolism [63]. Insulin regulates neuronal development, modulates neurotransmitter signaling pathways, and participates in learning and memory [64, 65]. Regarding memory, insulin activates signaling cascades in the hippocampus that affect synaptic plasticity [66]. Insulin resistance in the CNS has recently been found to cause anxious states, hyperphagia, and depressive-like behaviors [67]. Insulin resistance can be evaluated through the ratio between the serine-phosphorylated insulin receptor substrate with respect to the total phosphorylated insulin receptor substrate, in the brain or peripheral tissues. A greater ratio indicates increased insulin resistance [9, 68]. This marker, together with ex vivo stimulation of brain tissue with insulin, was employed to demonstrate brain insulin resistance in AD patients [9, 69].

Peripheral insulin resistance (hyperinsulinemia) decreases glucose sensitivity in major target organs such as muscles, liver, and adipose tissue. In this context, there is an increase in the amount of insulin available in the bloodstream, which consequently increases tolerance to glucose [70]. Several findings suggest that the development of these alterations would be associated with mitochondrial dysfunction and/or ER stress due to aging [71, 72].

Hyperinsulinemia is a risk factor for the development of hyperglycemia and type II diabetes (DTII). It is associated with a higher risks of neurodegeneration [15, 50, 73,74,75], due to a decreased degradation of amyloid beta, because the augment in the insulin sequesters by the insulin degrading enzyme (IDE).

It is also associated with an increase in CDK5 activity and, with it, the hyperphosphorylation of tau that is involved in AD [15].

Currently, presenting AD is considered to have a higher risk of DTII [76] and vice versa [36]. It is very possible to go from mild cognitive impairment to AD if glucose metabolism is altered [58, 77]. This has been evidenced as the disease progresses [78,79,80]. Other studies suggest an association between abnormal tau phosphorylation and insulin resistance [81]. Both diseases are related to changes in the expression of glucose transporters and in particular AD with a decrease in available energy in neurons [82]. However, the latter is still controversial, as other studies showed no relation between diabetes TII and the formation of neurofibrillary tangles (NFT) and Ab peptide in diabetic postmortem brains [83]. Nevertheless, it should be considered that this study relates to the APOE genotype and not the sporadic AD. Thus, it is possible that although glucose metabolism impairment can relate to neurodegenerative diseases, the mechanism is still inconclusive.

In the CNS, glucose bioavailability is limited by crossing the blood-brain barrier (BBB), mediated by glucose transporters GLUT1-6 and GLUT-8 and sodium-dependent transporters (SGLT1) to reach neurons and glia [82, 84,85,86]. Another energy source is lactate derived from astrocytes [87,88,89] and brain ketones [90].

In regard to the glucose transporters, the GLUT1 transporter is expressed in the endothelial cells of the BBB [91, 92]; GLUT3, on the other hand, is expressed in neurons with high affinity to glucose [93, 94], and GLUT4 is expressed in the BBB of the ventromedial hypothalamus [95] and temporal cortex; therefore, it participates in memory and cognition processes [96]. Both GLUT1 and GLUT3 are insulin independent for membrane translocation [97]. GLUT3 and GLUT4 transporters decrease their expression with aging [98].

Impairments in glucose metabolism have been reported to cause memory impairment and hippocampal atrophy [99]. However, the exact molecular mechanisms that associate the origin of AD disease with glucose and insulin metabolic alterations are still unclear [36].

Several avenues regarding treatments for insulin resistance and TII diabetes have shown an effect on AD, for example, receptor agonists for incretin (IRA) such as semaglutide, which is shown not to cross the BBB. However, this compound is still one of the most promising single IRA in the treatment of AD and Parkinson’s disease, since it is one of the most stable IRA [100]. Metformin, on the other hand, is a biguanide used as an oral antidiabetic drug. In AD, it has been demonstrated that it can act as an activator of chaperone-mediated autophagy in a mouse AD model [101]. It should be noted that autophagy is a key process in neurodegenerative diseases, as it is considered a hunter of aggregates [102]. The latter opens new therapeutic approaches that seek to induce autophagy in neurodegenerative diseases [103]. Intranasal insulin is a novel treatment for TII diabetes, which has demonstrated promising results in AD, as it improves brain insulin signaling and, consequently, ameliorates the cognitive performance and metabolic integrity of the brain in patients with AD [104].

All the latter are consistent with an association between glucose metabolism impairment and AD. Furthermore, use of fluoro (F18)-2-deoxy-d-glucose (FDG)-PET, which involves a glucose analog to evaluate carbohydrate metabolism in the brain, has been proposed as a potential biomarker [105].

Tau post-translational modifications

Microtubule-associate protein tau

Tau protein is a microtubule-binding protein described as a MAP that binds tubulin [106]. Due to the plasticity of its encoding gene (Chr. 17, region 17q 21 in humans), some of its exons (2, 3, 4A, 6, 8, 10, and 14) can be processed by alternative splicing, thus generating several isoforms [107]. In humans, 6 isoforms have been described, which consists of two domains, an amino terminal domain and a carboxy-terminal domain [108]. The first one is denominated “projection domain,” which is rich in proline and it also has an acid region. The C-terminal is the principal binding domain of tau, and it contains three (3R) or four (4R) internal repeats [108].

In the central nervous system, tau under normal conditions provides stability to the microtubules (MT) and articulates the transport system of signaling molecules and cellular components [109]. Those functions are disrupted during the course of AD, due to several changes in the pattern of post-translational modifications.

Post-translational modifications

Tau protein can suffer phosphorylations, methylations, ubiquitinations, and glycosylation/truncation, post-translational modifications that generate different tau variants.

Phosphorylation

Tau has over 30 aa that can be phosphorylated, which includes ser, thr, and tyr [110]. In AD, tau is hyperphosphorylated, which captures native tau and other microtubules-associated proteins, causing the disassembly of microtubules [110].

Subsequently, there is a destabilization of the cytoskeleton, produced by the alteration of tau-dependent cellular functions, such as vesicular and organelle transport, axonal growth, and nerve signal propagation. This anomaly is known as tauopathies and is present in many neurodegenerative diseases [111]. There are 20 diseases categorized as tauopathies, which are sub-divided into two groups, a primary and a secondary; Alzheimer disease is part of the secondary group, and it is also the most preponderant [111]. The secondary group is characterized for the presence of both intracellular tau pathology and extracellular amyloid plaque deposits [111]. The particularity of this tauopathy is the formation of insoluble deposits called neurofibrillary tangles (NFT) in the three (3R) and four (4R) isoforms [112]. The dysfunctionality caused by NFT is manifested from the soma to the dendrites, and the most commonly affected regions of the brain are the entorhinal cortex, the hippocampus, and the neocortex [112].

Studies have demonstrated how an increased activity of kinases, such as CDK5, and downregulation of phosphatases influences tau hyperphosphorylation, leading to the oligomer formation of tau [113, 114]. The deregulation of CDK5 is due to the formation of CDK5/p25 complex, product of p35 splitting, possibly as a result of oxidative stress and amyloid peptides to which the neuron has been exposed [115, 116]. The latter leads to the proteolysis of p35, transforming into p25, a fragment of the protein that is neurotoxic and has an active and a totally extended conformation [115]. The conformational change that took place and the generation of p25 impacts the way CDK5 activates, given the fact that the latter activation lasts longer than p35 [115]. This conversion results in CDK5 hyperactivity and subsequently, a possible hyperphosphorylation of tau protein and neurofilaments, along with a cytoskeletal alteration and eventually neuronal death [117].

Their conformational structure changes from an a-helix to a b-sheet structure, which facilitates the formation of the oligomers [20].

The latter is the basis of the neuroimmunomodulation theory, proposed by our laboratory [118,119,120]. Indeed, fragments from paired-helical filaments (PHF) (with hyperphosphorylated tau) and other molecules (such as Ab peptides and advanced glycation end products (AGEs)) may act as a “danger signal,” activating the resting microglia [120, 121]. Activated microglia increases the pro-inflammatory signaling through the NFkb pathway, leading to the increased activation of several kinases, such as CDK5 and GSK3b [122]. The latter increases tau phosphorylation, in a cyclic course of events that eventually leads to chronic neuroinflammation and neurodegeneration [122].

It should be noted, however, that not only the hyperphosphorylation is pivotal on AD, but also which of the putative phosphorylation sites are target of the kinases. Furthermore, it was demonstrated in vitro that oxidative stress promotes tau dephosphorylation at the Tau1 epitope in SHSY5Y cells [123]. The latter was dependent on the activity of the cdk5/p35 complex, since an increase in the substrate phosphorylation as well as for the complex association was observed [123]. Also, oxidative stress induced a decrease in the amount of inhibitor-2 bound to phosphatase PP1, associated to an increased phosphorylation of the inhibitor-2 protein.

Thus, hyperphosphorylation of tau relies in a shift of balance between the kinases and phosphatases, in which the upregulation of the kinases activity exceeds the phosphatase activity.

Methylation

Methylation is the enzymatic addition of methyl (CH3) groups to protein substrates [124]. In this case, methyltransferases transfers the methyl group from the s-adenosyl methionine to the target residues: lysine or arginine [124]. In tau protein, this post-translational modification can play different roles during the pathological processes leading to AD [22]. It has been described lysine methylation is an endogenous post-translational modification that modulates tau aggregation [22]. In vitro studies showed that Lys methylation impaired total filament length in a stoichiometry-dependent manner [22]. Moreover, mono-methylation and di-methylation of tau are related to normal aging and AD, respectively [22]. It should be noted that several lys are next to ser/thr, which are the key aa involved in phosphorylation.

In a mass spectrometry analysis of PHFs derived from AD brains, several lysine residues were detected distributed in the projection domain and the microtubule-binding domain (MBD), which are susceptible to be methylated [125]. Also, aggregated tau derived from AD brains is monomethylated at seven lysine residues in the proline-rich region and the R1/R2 repeats of the MBD [125]. Of these residues, the most frequently methylated ones are K180 and K267, in contrast to K290 which is has the lowest level of methylation [125]. Interestingly, in PHF-tau, phosphorylation of S262, which reduces tau affinity for microtubules, is found more frequently in the presence of methylated K267 [125].

Also, in PHF-tau, another residue, K254, was found to be mainly methylated and, in a lesser extent, ubiquitylated [125]. The latter suggests that methylation may prevent tau degradation by the proteasome.

All the latter suggests that tau lysine mono-methylation leads to a confirmation that allows self-assembly and aggregation. Considering lysine methylation is an apolar post-translational modification, it could be possible that the shift in the patter of methylation, from di-methylated to mono-methylated, exposes the residues susceptible for phosphorylation, blocking the residues for ubiquitination and, consequently, will be susceptible for self-assembly.

Ubiquitination

The quality control of the proteins realized by the ubiquitin-proteasome system (UPS) is fundamental. Ubiquitination is the specific binding of ubiquitin, a small 8.6 kDa regulatory protein to tag proteins for degradation by the UPS. Proteins that will be eliminated are poly-ubiquitinated and identified by the proteasome for their degradation [126].

As several other neurodegenerative diseases, a major trademark of AD is the accumulation of misfolded proteins. In non-pathological conditions, tau is ubiquitinated and processed in the proteasome [127]. In AD, it has been demonstrated that the ubiquitin-proteasome pathway is impaired and dysfunctional [128]. Since the ubiquitin-proteasome system is pivotal in tau degradation, its impairment leads, consequently, to tau accumulation [129]. It should be noted that the first step in the ubiquitin-proteasome system is the activation of ubiquitin in an ATP-dependent manner, mediated by the ubiquitin-activating enzyme (E1) [130]. Thus, if less intracellular ATP is generated due to the mitochondrial dysfunction, less ubiquitination will occur. This would explain, at least in part, the accumulation of aggregated tau proteins.

Glycosylation/truncation

These modifications include glycosylation and truncation, both of which occur in early stages of AD.

In regard to glycosylation, this post-translational modification is the covalent attachment of oligosaccharides to a protein, tau in this case. Glycosylation of tau protein was non-physiological in the brain of AD patients, and this abnormal pattern of glycosylation was not detected in control patients [131]. In other study, Liu et al. [132] have shown that abnormal in vitro glycosylation modulates the phosphorylation of tau by the kinases PKA, GSK-3, and CDK-5, which, in turn, inhibits dephosphorylation by the phosphatases PP2A and PP5 [133]. The latter is closely related to the negative correlation between O-glycosylation of tau and its phosphorylation [132, 134]; thus, interaction between many post-translational modifications may be necessary to induce the oligomer tau formation.

Truncation is another post-translational modification that enhance the capacity of tau to aggregate [135]. In AD patients’ brains, this process occurs in D13, E391, and D421 [136]. The latter leads to an accumulation of tau protein truncated at D13, E391, and D421, which correlates with AD progression [136]. These truncated tau forms are found in PHFs [137], and tau cleavage occurs after its hyperphosphorylation [138]. Indeed, an in vitro model of ethanol-induced neuronal apoptosis, tau hyperphosphorylation, occurs before its cleavage, and both tau hyperphosphorylation and apoptosis are blocked by lithium [138].

Neuroinflammatory mechanisms involved in microglial activation

Extracellular ATP role

ATP is an intracellular signaling molecule, released into the extracellular medium when there is damage to the CNS from injured cells. Extracellular ATP activates the microglia through P2X (ionotropic) purinergic receptors [139] and induces cytokine release in the microglia [140]. In the CNS, ATP is released from glial cells and nerve terminals, functioning as a neurotransmitter or intracellular signaling [139].

Microglia migrates to where the damage is by promoting tissue repair but in turn propels excess inflammatory processes and can release neurotoxic factors that can increase neurodegeneration [141].

Extracellular ATP is a key player in the control of neuronal activity through a microglia-driven negative feedback [142]. Indeed, microglia suppresses neuronal activation through its capacity to sense and catabolize extracellular ATP, which is released upon neuronal activation by astrocytes and neurons [142]. ATP is catabolized by the microglial hydrolyzing enzymes CD39 and CD73 into AMP and adenosine respectively. Adenosine, then, suppresses the neuronal activity via the adenosine receptor A present in neurons, thus establishing the microglia-mediated negative feedback mechanism [142].

In a β-amyloid (Aβ1-42)-based mouse model of early AD, it has been demonstrated an increased release of ATP from neurons coupled to an increased density and activity of ecto-5′-nucleotidase (CD73)-mediated formation of adenosine selectively activating A2AR [143]. Moreover, CD73 inhibition impaired long-term potentiation (LTP) in mouse hippocampal slices [143].

All the later suggests that extracellular ATPs, and more specifically, adenosine, are danger signals that might be involved in synaptic loss. Consistent with the latter, ATP release from nerve terminals is increased after intracerebroventricular Aβ1-42 administration, together with CD73 and A2AR upregulation in hippocampal synapses. Importantly, this increased CD73 activity is critically required for Aβ1-42 to impair synaptic plasticity and memory since Aβ1-42-induced synaptic and memory deficits were eliminated in CD73-KO mice [143]. These observations establish a key regulatory role of CD73 activity over neuronal A2AR and imply CD73 as a novel target for modulation of early AD. On the other hand, a 50% decrease in ATP production has been observed in late-onset AD [79]. The latter is also linked to decreased glucose uptake and decreased ubiquitination.

It should be noted, however, that all the mechanisms mentioned above are indirect effects and further studies are required to fully stablish the role of extracellular ATP in AD. For that, it would be relevant to evaluate the concentration of adenosine by fluorescence and the activity of the receptors by electrophysiology.

Conclusions

The influence of glucose metabolism is evident in several aspects of AD. First is through insulin resistance and diabetes with ER stress supported by medical evidence. This is also consistent with the fact that ER stress is also part of the UPR when accumulation of misfolded proteins occurs, such as Aβ peptide, and tau protein in AD. A pivotal part of this mechanism is also the post-translational modifications as they are key regulators of protein folding and degradation. In the case of tau protein, methylation and phosphorylation are the main regulators of tau self-assembly and aggregation. But other post-translational modifications, such as ubiquitination, are also relevant. The glucose metabolism is also involved in neuroinflammatory mechanisms regarding neurodegeneration and extracellular ATP, which is the source for adenosine generation. Adenosine, through its receptor in the neurons, stops neuronal activity, thus promoting neuronal decline and upregulation of apoptotic pathways.

Then, there are several mechanisms that overlap and fail, facilitating the aggregation of tau protein. One of them is the regulation of the glucose mechanism and the concomitant loss of insulin sensitivity. Both alter the capacity of the ER by decreasing the amount of energy available. Together with this, the mechanisms to avoid protein aggregation, driven by the chaperone proteins in the ER, are insufficient [144]. In addition, by decreasing the amount of energy, the ubiquitination that tags tau for degradation decreases. All alterations of the protein are related to dysmetabolism. Both tau hyperphosphorylation and metabolic alterations are situated in an inflammatory scenario that promotes neurodegenerative processes by activating microglia [145]. If we consider all the summarized above, during the course of AD, glucose metabolism is a key mediator that promotes a metabolic dysfunction, which lead to protein aggregation, and consequently, neuronal death is gradually reached (Fig. 1). In this review, we highlight several mechanisms involving glucose metabolism impairment that act collectively in the etiology and progression of AD, which is why it is currently accepted that AD is a novel diabetes type 3.

Fig. 1
figure 1

Glucose metabolism and its involvement in AD. There are several mechanisms in which, directly or indirectly, glucose is involved in AD. (i) As a potential mechanism, a diagram with a general metabolic dysfunction that leads to an increased insulin resistance, and consequently, lower glucose uptake; (ii) in post-translational modifications in which glucose or glycans are required, such as methylation. These modifications also alter others post-translational modifications, such as phosphorylation and ubiquitination, which leads to tau aggregation and (iii) through the generation of ATP, that is released to the extracellular, where it can be sensed by microglia, and then transformed into adenosine. This adenosine suppresses neuronal activity and in the long term, causes synaptic dysfunction. ER, endoplasmic reticulum; ADP, adenosine di-phosphate; A2AR, adenosine receptor type 2; GLUT, glucose transporter ; PHF, paired helical filaments; CDK5, cyclin-dependent kinase type 5; CD73: 5′-nucleotidase; CD39, ectonucleoside triphosphate diphosphohydrolase-1

Availability of data and materials

Non-applicable.

Abbreviations

AD:

Alzheimer’s disease

NFT:

Neurofibrillary tangles

APP:

Amyloid precursor protein

UPR:

Unfolded protein response

APO-E:

Apolipoprotein E

GLUT:

Glucose transporters

ATP:

Adenosine-tri-phosphate

DTII:

Diabetes type 2

JNKs:

c-Jun N-terminal kinases

ER:

Endoplasmic reticulum

UP:

Unfolded proteins

ERAD:

Endoplasmic reticulum associated degradation

eIF2:

Elongation initiation factor-2

CNS:

Central nervous system

PI3K:

Phosphatidylinositol 3-kinase

MAPK:

Mitogen-activated protein kinase

GSK-3:

Glycosylation kinase

BBB:

Blood-brain barrier

MT:

Microtubules

PHF:

Paired-helical filaments

MBD:

Microtubule-binding domain

AGEs:

Advanced glycation end products

UPS:

Ubiquitin-proteasome system

LTP:

Long-term potentiation

References

  1. Guzman-Martinez L, Maccioni RB, Farias GA, Fuentes P, Navarrete LP. Biomarkers for Alzheimer’s disease. Curr Alzheimer Res. 2019;16:518–28.

    CAS  Article  PubMed  Google Scholar 

  2. Gong CX, Liu F, Grundke-Iqbal I, Iqbal K. Impaired brain glucose metabolism leads to Alzheimer neurofibrillary degeneration through a decrease in tau O-GlcNAcylation. J Alzheimers Dis. 2006;9:1–12.

    CAS  Article  PubMed  Google Scholar 

  3. Maccioni RB, et al. Inflammation: a major target for compounds to control Alzheimer’s disease. J Alzheimers Dis. 2020;76:1199–213.

    CAS  Article  PubMed  Google Scholar 

  4. Folch J, et al. The involvement of peripheral and brain insulin resistance in late onset Alzheimer’s dementia. Front Aging Neurosci. 2019;11:236.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. Klosinski LP, et al. White matter lipids as a ketogenic fuel supply in aging female brain: implications for Alzheimer’s disease. EBioMedicine. 2015;2:1888–904.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Chaudhari N, Talwar P, Parimisetty A, Lefebvre d’Hellencourt C, Ravanan P. A molecular web: endoplasmic reticulum stress, inflammation, and oxidative stress. Front Cell Neurosci. 2014;8:213.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Isaev NK, Stelmashook EV, Genrikhs EE. Neurogenesis and brain aging. Rev Neurosci. 2019;30:573–80.

    Article  PubMed  Google Scholar 

  8. Yan X, Hu Y, Wang B, Wang S, Zhang X. Metabolic dysregulation contributes to the progression of Alzheimer’s disease. Front Neurosci. 2020;14:530219.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Talbot K, et al. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest. 2012;122:1316–38.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Sweeney MD, Sagare AP, Zlokovic BV. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol. 2018;14:133–50.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Maurer K, Hoyer S. Alois Alzheimer revisited: differences in origin of the disease carrying his name. J Neural Transm (Vienna). 2006;113:1645–58.

    CAS  Article  Google Scholar 

  12. Magistretti PJ, Allaman I. Lactate in the brain: from metabolic end-product to signalling molecule. Nat Rev Neurosci. 2018;19:235–49.

    CAS  Article  PubMed  Google Scholar 

  13. Havrankova J, Roth J, Brownstein M. Insulin receptors are widely distributed in the central nervous system of the rat. Nature. 1978;272:827–9.

    CAS  Article  PubMed  Google Scholar 

  14. Fernandez AM, Torres-Aleman I. The many faces of insulin-like peptide signalling in the brain. Nat Rev Neurosci. 2012;13:225–39.

    CAS  Article  PubMed  Google Scholar 

  15. Neumann KF, et al. Insulin resistance and Alzheimer’s disease: molecular links & clinical implications. Curr Alzheimer Res. 2008;5:438–47.

    CAS  Article  PubMed  Google Scholar 

  16. Frisardi V, et al. Metabolic-cognitive syndrome: a cross-talk between metabolic syndrome and Alzheimer’s disease. Ageing Res Rev. 2010;9:399–417.

    Article  PubMed  Google Scholar 

  17. Zhang J, et al. An updated meta-analysis of cohort studies: diabetes and risk of Alzheimer’s disease. Diabetes Res Clin Pract. 2017;124:41–7.

    Article  PubMed  Google Scholar 

  18. Zhu W, et al. Endoplasmic reticulum stress may be involved in insulin resistance and lipid metabolism disorders of the white adipose tissues induced by high-fat diet containing industrial trans-fatty acids. Diabetes Metab Syndr Obes. 2019;12:1625–38.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Amen OM, Sarker SD, Ghildyal R, Arya A. Endoplasmic reticulum stress activates unfolded protein response signaling and mediates inflammation, obesity, and cardiac dysfunction: therapeutic and molecular approach. Front Pharmacol. 2019;10:977.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Fichou Y, Eschmann NA, Keller TJ, Han S. Conformation-based assay of tau protein aggregation. Methods Cell Biol. 2017;141:89–112.

    CAS  Article  PubMed  Google Scholar 

  21. Martin L, Latypova X, Terro F. Post-translational modifications of tau protein: implications for Alzheimer’s disease. Neurochem Int. 2011;58:458–71.

    CAS  Article  PubMed  Google Scholar 

  22. Huseby CJ, et al. Quantification of tau protein lysine methylation in aging and Alzheimer’s disease. J Alzheimers Dis. 2019;71:979–91.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Marcelli S, et al. The involvement of post-translational modifications in Alzheimer’s disease. Curr Alzheimer Res. 2018;15:313–35.

    CAS  Article  PubMed  Google Scholar 

  24. Liu Y, Liu F, Iqbal K, Grundke-Iqbal I, Gong CX. Decreased glucose transporters correlate to abnormal hyperphosphorylation of tau in Alzheimer disease. FEBS Lett. 2008;582:359–64.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Thul PJ, et al. A subcellular map of the human proteome. Science. 2017;356(6340):eaal3321.

    Article  CAS  PubMed  Google Scholar 

  26. Pfeffer SR, Rothman JE. Biosynthetic protein transport and sorting by the endoplasmic reticulum and Golgi. Annu Rev Biochem. 1987;56:829–52.

    CAS  Article  PubMed  Google Scholar 

  27. Sitia R, Braakman I. Quality control in the endoplasmic reticulum protein factory. Nature. 2003;426:891–4.

    CAS  Article  PubMed  Google Scholar 

  28. Martinez-Cue C, Rueda N. Cellular senescence in neurodegenerative diseases. Front Cell Neurosci. 2020;14:16.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Mohan S, Preetha Rani MR, Brown L, Ayyappan P, Raghu KG. Endoplasmic reticulum stress: a master regulator of metabolic syndrome. Eur J Pharmacol. 2019;860:172553.

    CAS  Article  PubMed  Google Scholar 

  30. Marciniak SJ, Ron D. Endoplasmic reticulum stress signaling in disease. Physiol Rev. 2006;86:1133–49.

    CAS  Article  PubMed  Google Scholar 

  31. Gerakis Y, Hetz C. Emerging roles of ER stress in the etiology and pathogenesis of Alzheimer’s disease. FEBS J. 2018;285:995–1011.

    CAS  Article  PubMed  Google Scholar 

  32. Roussel BD, et al. Endoplasmic reticulum dysfunction in neurological disease. Lancet Neurol. 2013;12:105–18.

    CAS  Article  PubMed  Google Scholar 

  33. Needham PG, Guerriero CJ, Brodsky JL. Chaperoning endoplasmic reticulum-associated degradation (ERAD) and protein conformational diseases. Cold Spring Harb Perspect Biol. 2019;11(8):a033928.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Ruggiano A, Foresti O, Carvalho P. Quality control: ER-associated degradation: protein quality control and beyond. J Cell Biol. 2014;204:869–79.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Meunier L, Usherwood YK, Chung KT, Hendershot LM. A subset of chaperones and folding enzymes form multiprotein complexes in endoplasmic reticulum to bind nascent proteins. Mol Biol Cell. 2002;13:4456–69.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Frozza RL, Lourenco MV, De Felice FG. Challenges for Alzheimer’s disease therapy: insights from novel mechanisms beyond memory defects. Front Neurosci. 2018;12:37.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Dufey E, Sepulveda D, Rojas-Rivera D, Hetz C. Cellular mechanisms of endoplasmic reticulum stress signaling in health and disease. 1. An overview. Am J Physiol Cell Physiol. 2014;307:C582–94.

    CAS  Article  PubMed  Google Scholar 

  38. Hetz C, Saxena S. ER stress and the unfolded protein response in neurodegeneration. Nat Rev Neurol. 2017;13:477–91.

    CAS  Article  PubMed  Google Scholar 

  39. Cornejo VH, Pihan P, Vidal RL, Hetz C. Role of the unfolded protein response in organ physiology: lessons from mouse models. IUBMB Life. 2013;65:962–75.

    CAS  Article  PubMed  Google Scholar 

  40. Katayama T, et al. Induction of neuronal death by ER stress in Alzheimer’s disease. J Chem Neuroanat. 2004;28:67–78.

    CAS  Article  PubMed  Google Scholar 

  41. Waldherr SM, Strovas TJ, Vadset TA, Liachko NF, Kraemer BC. Constitutive XBP-1s-mediated activation of the endoplasmic reticulum unfolded protein response protects against pathological tau. Nat Commun. 2019;10:4443.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Saxena S, Caroni P. Selective neuronal vulnerability in neurodegenerative diseases: from stressor thresholds to degeneration. Neuron. 2011;71:35–48.

    CAS  Article  PubMed  Google Scholar 

  43. Nestler EJ. Neuropharmacology: molecular neuropharmacology: a foundation for clinical neuroscience; 2008.

    Google Scholar 

  44. Marchetti P, et al. The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients. Diabetologia. 2007;50:2486–94.

    CAS  Article  PubMed  Google Scholar 

  45. Harding HP, et al. Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival. Mol Cell. 2001;7:1153–63.

    CAS  Article  PubMed  Google Scholar 

  46. Hoozemans JJ, et al. The unfolded protein response is activated in pretangle neurons in Alzheimer’s disease hippocampus. Am J Pathol. 2009;174:1241–51.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Yang W, et al. Repression of the eIF2alpha kinase PERK alleviates mGluR-LTD impairments in a mouse model of Alzheimer’s disease. Neurobiol Aging. 2016;41:19–24.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Kroner Z. The relationship between Alzheimer’s disease and diabetes: type 3 diabetes? Altern Med Rev. 2009;14:373–9.

    PubMed  Google Scholar 

  49. Vasiljevic J, Torkko JM, Knoch KP, Solimena M. The making of insulin in health and disease. Diabetologia. 2020;63:1981–9.

    Article  PubMed  PubMed Central  Google Scholar 

  50. van der Heide LP, Ramakers GM, Smidt MP. Insulin signaling in the central nervous system: learning to survive. Prog Neurobiol. 2006;79:205–21.

    Article  CAS  PubMed  Google Scholar 

  51. Csajbok EA, Tamas G. Cerebral cortex: a target and source of insulin? Diabetologia. 2016;59:1609–15.

    CAS  Article  PubMed  Google Scholar 

  52. Rubenstein AH, Melani F, Pilkis S, Steiner DF. Proinsulin. Secretion, metabolism, immunological and biological properties. Postgrad Med J. 1969;45(Suppl):476–81.

    Google Scholar 

  53. Shafqat J, et al. Proinsulin C-peptide elicits disaggregation of insulin resulting in enhanced physiological insulin effects. Cell Mol Life Sci. 2006;63:1805–11.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. Kullmann S, et al. Brain insulin resistance at the crossroads of metabolic and cognitive disorders in humans. Physiol Rev. 2016;96:1169–209.

    CAS  Article  PubMed  Google Scholar 

  55. Baskin DG, et al. Insulin receptor substrate-1 (IRS-1) expression in rat brain. Endocrinology. 1994;134:1952–5.

    CAS  Article  PubMed  Google Scholar 

  56. Leroy K, Brion JP. Developmental expression and localization of glycogen synthase kinase-3beta in rat brain. J Chem Neuroanat. 1999;16:279–93.

    CAS  Article  PubMed  Google Scholar 

  57. Gregg EW, et al. Is diabetes associated with cognitive impairment and cognitive decline among older women? Study of Osteoporotic Fractures Research Group. Arch Intern Med. 2000;160:174–80.

    CAS  Article  PubMed  Google Scholar 

  58. White MF. Insulin signaling in health and disease. Science. 2003;302:1710–1.

    CAS  Article  PubMed  Google Scholar 

  59. Baskin DG, Porte D Jr, Guest K, Dorsa DM. Regional concentrations of insulin in the rat brain. Endocrinology. 1983;112:898–903.

    CAS  Article  PubMed  Google Scholar 

  60. Havrankova J, Brownstein M, Roth J. Insulin and insulin receptors in rodent brain. Diabetologia. 1981;20:268–73.

    CAS  Article  PubMed  Google Scholar 

  61. Unger JW, Livingston JN, Moss AM. Insulin receptors in the central nervous system: localization, signalling mechanisms and functional aspects. Prog Neurobiol. 1991;36:343–62.

    CAS  Article  PubMed  Google Scholar 

  62. van Houten M, Posner BI, Kopriwa BM, Brawer JR. Insulin-binding sites in the rat brain: in vivo localization to the circumventricular organs by quantitative radioautography. Endocrinology. 1979;105:666–73.

    Article  PubMed  Google Scholar 

  63. Schubert M, et al. Role for neuronal insulin resistance in neurodegenerative diseases. Proc Natl Acad Sci U S A. 2004;101:3100–5.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. McNay EC, Recknagel AK. Brain insulin signaling: a key component of cognitive processes and a potential basis for cognitive impairment in type 2 diabetes. Neurobiol Learn Mem. 2011;96:432–42.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. Gerozissis K. Brain insulin, energy and glucose homeostasis; genes, environment and metabolic pathologies. Eur J Pharmacol. 2008;585:38–49.

    CAS  Article  PubMed  Google Scholar 

  66. Spinelli M, Fusco S, Grassi C. Brain insulin resistance and hippocampal plasticity: mechanisms and biomarkers of cognitive decline. Front Neurosci. 2019;13:788.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Kleinridders A, Pothos EN. Impact of brain insulin signaling on dopamine function, food intake, reward, and emotional behavior. Curr Nutr Rep. 2019;8:83–91.

    CAS  Article  PubMed  Google Scholar 

  68. Kellar D, Craft S. Brain insulin resistance in Alzheimer’s disease and related disorders: mechanisms and therapeutic approaches. Lancet Neurol. 2020;19:758–66.

    CAS  Article  PubMed  Google Scholar 

  69. Yarchoan M, et al. Abnormal serine phosphorylation of insulin receptor substrate 1 is associated with tau pathology in Alzheimer’s disease and tauopathies. Acta Neuropathol. 2014;128:679–89.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. Chakrabarty K, Bhattacharyya S, Christopher R, Khanna S. Glutamatergic dysfunction in OCD. Neuropsychopharmacology. 2005;30:1735–40.

    CAS  Article  PubMed  Google Scholar 

  71. Jeschke MG, et al. Severe injury is associated with insulin resistance, endoplasmic reticulum stress response, and unfolded protein response. Ann Surg. 2012;255:370–8.

    Article  PubMed  Google Scholar 

  72. Moltedo O, Remondelli P, Amodio G. The mitochondria-endoplasmic reticulum contacts and their critical role in aging and age-associated diseases. Front Cell Dev Biol. 2019;7:172.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Ott A, et al. Diabetes mellitus and the risk of dementia: the Rotterdam study. Neurology. 1999;53:1937–42.

    CAS  Article  PubMed  Google Scholar 

  74. Matsuzaki T, et al. Insulin resistance is associated with the pathology of Alzheimer disease: the Hisayama study. Neurology. 2010;75:764–70.

    CAS  Article  PubMed  Google Scholar 

  75. Crane PK, et al. Glucose levels and risk of dementia. N Engl J Med. 2013;369:540–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. Janson J, et al. Increased risk of type 2 diabetes in Alzheimer disease. Diabetes. 2004;53:474–81.

    CAS  Article  PubMed  Google Scholar 

  77. Benedict C, Grillo CA. Insulin resistance as a therapeutic target in the treatment of Alzheimer’s disease: a state-of-the-art review. Front Neurosci. 2018;12:215.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Chase TN, et al. Regional cortical dysfunction in Alzheimer’s disease as determined by positron emission tomography. Ann Neurol. 1984;15(Suppl):S170–4.

    Article  PubMed  Google Scholar 

  79. Shah K, Desilva S, Abbruscato T. The role of glucose transporters in brain disease: diabetes and Alzheimer’s Disease. Int J Mol Sci. 2012;13:12629–55.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. Chen Y, Deng Y, Zhang B, Gong CX. Deregulation of brain insulin signaling in Alzheimer’s disease. Neurosci Bull. 2014;30:282–94.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. Liu Y, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX. Brain glucose transporters, O-GlcNAcylation and phosphorylation of tau in diabetes and Alzheimer’s disease. J Neurochem. 2009;111:242–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. Koepsell H. Glucose transporters in brain in health and disease. Pflugers Arch. 2020;472:1299–343.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. Shinohara M, et al. Interaction between APOE genotype and diabetes in cognitive decline. Alzheimers Dement (Amst). 2020;12:e12006.

    Google Scholar 

  84. Choeiri C, Staines W, Messier C. Immunohistochemical localization and quantification of glucose transporters in the mouse brain. Neuroscience. 2002;111:19–34.

    CAS  Article  PubMed  Google Scholar 

  85. Douard V, Ferraris RP. Regulation of the fructose transporter GLUT5 in health and disease. Am J Physiol Endocrinol Metab. 2008;295:E227–37.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. Gomez O, Ballester-Lurbe B, Poch E, Mesonero JE, Terrado J. Developmental regulation of glucose transporters GLUT3, GLUT4 and GLUT8 in the mouse cerebellar cortex. J Anat. 2010;217:616–23.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  87. Ding F, Yao J, Rettberg JR, Chen S, Brinton RD. Early decline in glucose transport and metabolism precedes shift to ketogenic system in female aging and Alzheimer’s mouse brain: implication for bioenergetic intervention. PLoS One. 2013;8:e79977.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. Magistretti PJ, Pellerin L. Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging. Philos Trans R Soc Lond B Biol Sci. 1999;354:1155–63.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. Magistretti PJ, Pellerin L. Astrocytes couple synaptic activity to glucose utilization in the brain. News Physiol Sci. 1999;14:177–82.

    CAS  PubMed  Google Scholar 

  90. Guzmán M, Blázquez C. Is there an astrocyte- neuron ketone body shuttle? Trends Endocrinol Metab. 2001;12:169–73.

    Article  PubMed  Google Scholar 

  91. Hernandez-Garzon E, et al. The insulin-like growth factor I receptor regulates glucose transport by astrocytes. Glia. 2016;64:1962–71.

    Article  PubMed  Google Scholar 

  92. Soans RE, Lim DC, Keenan BT, Pack AI, Shackleford JA. Automated protein localization of blood brain barrier vasculature in brightfield IHC images. PLoS One. 2016;11:e0148411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Gerhart DZ, Broderius MA, Borson ND, Drewes LR. Neurons and microvessels express the brain glucose transporter protein GLUT3. Proc Natl Acad Sci U S A. 1992;89:733–7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. Shawahna R, et al. Transcriptomic and quantitative proteomic analysis of transporters and drug metabolizing enzymes in freshly isolated human brain microvessels. Mol Pharm. 2011;8:1332–41.

    CAS  Article  PubMed  Google Scholar 

  95. Ngarmukos C, Baur EL, Kumagai AK. Co-localization of GLUT1 and GLUT4 in the blood-brain barrier of the rat ventromedial hypothalamus. Brain Res. 2001;900:1–8.

    CAS  Article  PubMed  Google Scholar 

  96. Mosconi L. Brain glucose metabolism in the early and specific diagnosis of Alzheimer’s disease. FDG-PET studies in MCI and AD. Eur J Nucl Med Mol Imaging. 2005;32:486–510.

    CAS  Article  PubMed  Google Scholar 

  97. Ferreira IA, et al. Glucose uptake via glucose transporter 3 by human platelets is regulated by protein kinase B. J Biol Chem. 2005;280:32625–33.

    CAS  Article  PubMed  Google Scholar 

  98. Jais A, et al. Myeloid-cell-derived VEGF maintains brain glucose uptake and limits cognitive impairment in obesity. Cell. 2016;165:882–95.

    CAS  Article  PubMed  Google Scholar 

  99. Convit A, Wolf OT, Tarshish C, de Leon MJ. Reduced glucose tolerance is associated with poor memory performance and hippocampal atrophy among normal elderly. Proc Natl Acad Sci U S A. 2003;100:2019–22.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  100. Salameh TS, Rhea EM, Talbot K, Banks WA. Brain uptake pharmacokinetics of incretin receptor agonists showing promise as Alzheimer’s and Parkinson’s disease therapeutics. Biochem Pharmacol. 2020;180:114187.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  101. Xu X, et al. Metformin activates chaperone-mediated autophagy and improves disease pathologies in an Alzheimer disease mouse model. Protein Cell. 2021;12:769–87.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  102. Park H, Kang JH, Lee S. Autophagy in neurodegenerative diseases: a hunter for aggregates. Int J Mol Sci. 2020;21(9):3369.

    CAS  Article  PubMed Central  Google Scholar 

  103. Djajadikerta A, et al. Autophagy induction as a therapeutic strategy for neurodegenerative diseases. J Mol Biol. 2020;432:2799–821.

    CAS  Article  PubMed  Google Scholar 

  104. Freiherr J, et al. Intranasal insulin as a treatment for Alzheimer’s disease: a review of basic research and clinical evidence. CNS Drugs. 2013;27:505–14.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. Smailagic N, et al. (1)(8)F-FDG PET for the early diagnosis of Alzheimer’s disease dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev. 2015;1:CD010632.

    PubMed  Google Scholar 

  106. Maccioni RB, Rivas CI, Vera JC. Differential interaction of synthetic peptides from the carboxyl-terminal regulatory domain of tubulin with microtubule-associated proteins. EMBO J. 1988;7:1957–63.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  107. Andreadis A. Tau gene alternative splicing: expression patterns, regulation and modulation of function in normal brain and neurodegenerative diseases. Biochim Biophys Acta. 2005;1739:91–103.

    CAS  Article  PubMed  Google Scholar 

  108. Miguel L, et al. Detection of all adult Tau isoforms in a 3D culture model of iPSC-derived neurons. Stem Cell Res. 2019;40:101541.

    CAS  Article  PubMed  Google Scholar 

  109. Guo T, Noble W, Hanger DP. Roles of tau protein in health and disease. Acta Neuropathol. 2017;133:665–704.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  110. Neddens J, et al. Phosphorylation of different tau sites during progression of Alzheimer’s disease. Acta Neuropathol Commun. 2018;6:52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Kovacs GG. Tauopathies. Handb Clin Neurol. 2017;145:355–68.

    Article  PubMed  Google Scholar 

  112. Brion JP. Neurofibrillary tangles and Alzheimer’s disease. Eur Neurol. 1998;40:130–40.

    CAS  Article  PubMed  Google Scholar 

  113. Kimura T, Ishiguro K, Hisanaga S. Physiological and pathological phosphorylation of tau by Cdk5. Front Mol Neurosci. 2014;7:65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Wang JZ, Xia YY, Grundke-Iqbal I, Iqbal K. Abnormal hyperphosphorylation of tau: sites, regulation, and molecular mechanism of neurofibrillary degeneration. J Alzheimers Dis. 2013;33(Suppl 1):S123–39.

    PubMed  Google Scholar 

  115. Cortes N, Guzman-Martinez L, Andrade V, Gonzalez A, Maccioni RB. CDK5: a unique CDK and its multiple roles in the nervous system. J Alzheimers Dis. 2019;68:843–55.

    Article  PubMed  Google Scholar 

  116. Sun KH, de Pablo Y, Vincent F, Shah K. Deregulated Cdk5 promotes oxidative stress and mitochondrial dysfunction. J Neurochem. 2008;107:265–78.

    CAS  Article  PubMed  Google Scholar 

  117. Maccioni RB, Otth C, Concha II, Munoz JP. The protein kinase Cdk5. Structural aspects, roles in neurogenesis and involvement in Alzheimer’s pathology. Eur J Biochem. 2001;268:1518–27.

    CAS  Article  PubMed  Google Scholar 

  118. Guzman-Martinez L, et al. Neuroinflammation as a common feature of neurodegenerative disorders. Front Pharmacol. 2019;10:1008.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  119. Maccioni RB, Rojo LE, Fernandez JA, Kuljis RO. The role of neuroimmunomodulation in Alzheimer’s disease. Ann N Y Acad Sci. 2009;1153:240–6.

    CAS  Article  PubMed  Google Scholar 

  120. Morales I, Guzman-Martinez L, Cerda-Troncoso C, Farias GA, Maccioni RB. Neuroinflammation in the pathogenesis of Alzheimer’s disease. A rational framework for the search of novel therapeutic approaches. Front Cell Neurosci. 2014;8:112.

    PubMed  PubMed Central  Google Scholar 

  121. Morales I, Jimenez JM, Mancilla M, Maccioni RB. Tau oligomers and fibrils induce activation of microglial cells. J Alzheimers Dis. 2013;37:849–56.

    CAS  Article  PubMed  Google Scholar 

  122. Rojo LE, Fernandez JA, Maccioni AA, Jimenez JM, Maccioni RB. Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer’s disease. Arch Med Res. 2008;39:1–16.

    CAS  Article  PubMed  Google Scholar 

  123. Zambrano CA, Egana JT, Nunez MT, Maccioni RB, Gonzalez-Billault C. Oxidative stress promotes tau dephosphorylation in neuronal cells: the roles of cdk5 and PP1. Free Radic Biol Med. 2004;36:1393–402.

    CAS  Article  PubMed  Google Scholar 

  124. Kontaxi C, Piccardo P, Gill AC. Lysine-directed post-translational modifications of tau protein in Alzheimer’s disease and related tauopathies. Front Mol Biosci. 2017;4:56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Thomas SN, et al. Dual modification of Alzheimer’s disease PHF-tau protein by lysine methylation and ubiquitylation: a mass spectrometry approach. Acta Neuropathol. 2012;123:105–17.

    CAS  Article  PubMed  Google Scholar 

  126. Blount JR, Burr AA, Denuc A, Marfany G, Todi SV. Ubiquitin-specific protease 25 functions in endoplasmic reticulum-associated degradation. PLoS One. 2012;7:e36542.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  127. Liu YH, et al. Proteasome inhibition increases tau accumulation independent of phosphorylation. Neurobiol Aging. 2009;30:1949–61.

    CAS  Article  PubMed  Google Scholar 

  128. Cao J, Zhong MB, Toro CA, Zhang L, Cai D. Endo-lysosomal pathway and ubiquitin-proteasome system dysfunction in Alzheimer’s disease pathogenesis. Neurosci Lett. 2019;703:68–78.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  129. Wang Y, Mandelkow E. Degradation of tau protein by autophagy and proteasomal pathways. Biochem Soc Trans. 2012;40:644–52.

    CAS  Article  PubMed  Google Scholar 

  130. Zheng Q, et al. Dysregulation of ubiquitin-proteasome system in neurodegenerative diseases. Front Aging Neurosci. 2016;8:303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Takahashi M, et al. Glycosylation of microtubule-associated protein tau in Alzheimer’s disease brain. Acta Neuropathol. 1999;97:635–41.

    CAS  Article  PubMed  Google Scholar 

  132. Liu F, Iqbal K, Grundke-Iqbal I, Gong CX. Involvement of aberrant glycosylation in phosphorylation of tau by cdk5 and GSK-3beta. FEBS Lett. 2002;530:209–14.

    CAS  Article  PubMed  Google Scholar 

  133. Liu F, et al. Role of glycosylation in hyperphosphorylation of tau in Alzheimer’s disease. FEBS Lett. 2002;512:101–6.

    CAS  Article  PubMed  Google Scholar 

  134. Liu F, Iqbal K, Grundke-Iqbal I, Hart GW, Gong CX. O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer’s disease. Proc Natl Acad Sci U S A. 2004;101:10804–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  135. Chung CW, et al. Proapoptotic effects of tau cleavage product generated by caspase-3. Neurobiol Dis. 2001;8:162–72.

    CAS  Article  PubMed  Google Scholar 

  136. Horowitz PM, et al. Early N-terminal changes and caspase-6 cleavage of tau in Alzheimer’s disease. J Neurosci. 2004;24:7895–902.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  137. Mena R, Edwards PC, Harrington CR, Mukaetova-Ladinska EB, Wischik CM. Staging the pathological assembly of truncated tau protein into paired helical filaments in Alzheimer’s disease. Acta Neuropathol. 1996;91:633–41.

    CAS  Article  PubMed  Google Scholar 

  138. Saito M, et al. Tau phosphorylation and cleavage in ethanol-induced neurodegeneration in the developing mouse brain. Neurochem Res. 2010;35:651–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  139. Inoue K, Hosoi J, Denda M. Extracellular ATP has stimulatory effects on the expression and release of IL-6 via purinergic receptors in normal human epidermal keratinocytes. J Invest Dermatol. 2007;127:362–71.

    CAS  Article  PubMed  Google Scholar 

  140. Hide I, et al. Extracellular ATP triggers tumor necrosis factor-alpha release from rat microglia. J Neurochem. 2000;75:965–72.

    CAS  Article  PubMed  Google Scholar 

  141. Davalos D, et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci. 2005;8:752–8.

    CAS  Article  PubMed  Google Scholar 

  142. Badimon A, et al. Negative feedback control of neuronal activity by microglia. Nature. 2020;586(7829):417–23.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  143. Goncalves FQ, et al. Synaptic and memory dysfunction in a beta-amyloid model of early Alzheimer’s disease depends on increased formation of ATP-derived extracellular adenosine. Neurobiol Dis. 2019;132:104570.

    CAS  Article  PubMed  Google Scholar 

  144. Gorantla NV, Chinnathambi S. Tau protein squired by molecular chaperones during Alzheimer’s disease. J Mol Neurosci. 2018;66:356–68.

    CAS  Article  PubMed  Google Scholar 

  145. Didonna A. Tau at the interface between neurodegeneration and neuroinflammation. Genes Immun. 2020;21:288–300.

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge the ICC team for the assistance provided in the course of the funding acquisition and management.

Funding

This research was funded by FONDEF grant ID19I10301 and PAI grant I7819020001, from ANID, Chile.

Author information

Affiliations

Authors

Contributions

Conceptualization of the manuscript, RBM, AG, MC; investigation, RBM, AG, MC.; writing—original draft preparation, RBM, CC, AG, MC.; writing—review and editing, RBM, AG, CC; visualization AG, MC.; supervision, RBM project leader, RBM, funding acquisition, RBM. The author(s) read and approved the final manuscript.

Corresponding author

Correspondence to Ricardo B. Maccioni.

Ethics declarations

Ethics approval and consent to participate

Non-applicable.

Consent for publication

Non-applicable.

Competing interests

The authors declare they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

González, A., Calfío, C., Churruca, M. et al. Glucose metabolism and AD: evidence for a potential diabetes type 3. Alz Res Therapy 14, 56 (2022). https://doi.org/10.1186/s13195-022-00996-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13195-022-00996-8

Keywords

  • Glucose metabolism impairment
  • Tau posttranslational modifications
  • Insulin resistance
  • ER stress
  • Alzheimer’s disease