Skip to main content
  • Review
  • Published:

Potential synergy between tau aggregation inhibitors and tau chaperonemodulators

Abstract

Tau is a soluble, microtubule-associated protein known to aberrantly formamyloid-positive aggregates. This pathology is characteristic for more than 15neuropathies, the most common of which is Alzheimer’s disease. Findingtherapeutics to reverse or remove this non-native tau state is of greatinterest; however, at this time only one drug is entering phase III clinicaltrials for treating tauopathies. Generally, tau manipulation by therapeutics caneither directly or indirectly alter tau aggregation and stability. Drugs thatbind and change the conformation of tau itself are largely classified asaggregation inhibitors, while drugs that alter the activity of a tau-effectorprotein fall into several categories, such as kinase inhibitors, microtubulestabilizers, or chaperone modulators. Chaperone inhibitors that have proveneffective in tau models include heat shock protein 90 inhibitors, heat shockprotein 70 inhibitors and activators, as well as inducers of heat shockproteins. While many of these compounds can alter tau levels and/or aggregationstates, it is possible that combining these approaches may produce the mostoptimal outcome. However, because many of these compounds have multipleoff-target effects or poor blood–brain barrier permeability, thedevelopment of this synergistic therapeutic strategy presents significantchallenges. This review will summarize many of the drugs that have beenidentified to alter tau biology, with special focus on therapeutics that preventtau aggregation and regulate chaperone-mediated clearance of tau.

Review

Therapeutic targeting of tau triage

Tauopathies, a class of neurodegenerative diseases including Alzheimer’sdisease, frontotemporal dementia, and progressive supranuclear palsy, arecharacterized by the pathological aggregation of hyperphosphorylated tau tanglesin the human brain [1]. Because aberrant protein accumulation is a hallmark of manyneurological diseases, and tau is one of many proteins that formdisease-associated aggregates, this can present a new challenge for finding anaggregation inhibitor specific for tau.

Studies have shown that several molecular chaperone families, known as heat shockproteins (Hsps), are involved with preventing tau aggregation [2, 3] or assisting in tau degradation [4]. These families, named for their general protein size in kiloDaltons,include Hsp70 and Hsp90, the smaller Hsp40, and small Hsps. Recently, a numberof small molecule inhibitors have been developed and studied for their roles inregulating the ATPase activities of Hsp70 and Hsp90. In addition, much of thedrug discovery efforts directed at tau are aimed at disrupting its aggregation;several aggregation inhibitors have been identified and their potential efficacyhas been shown using model systems. This review will discuss drugs that havebeen developed to modulate the chaperone repertoire, as well as recent advancesin therapeutics affecting tau aggregation. Table 1summarizes all of the drugs discussed in this review. We speculate that thesecompounds could be synergistic, such that aggregation disruption followed by tauclearance could be more beneficial than either effect alone. By creating moresoluble tau through inhibiting its aggregation, chaperones have a greateropportunity to bind to tau. This chaperone-bound tau can then be targeted fordegradation.

Table 1 List of drugs

Assays and rationale for tau aggregation inhibitors

Tau aggregation has been defined using multiple techniques, but three primaryassays are traditionally used. Two of these techniques, the thioflavinfluorescence stain and the Gallyas silver stain, are typically used to examinetau aggregates in tissue. These stains bind beta sheets, allowing formeasurements of tau amyloidogenicity [5]. Tau filaments are also often measured using electron microscopy,both in tissue and in vitro[6]. Biochemically, tau aggregation is measured using sequentialextractions with detergents, such as sarkosyl and sodium dodecyl sulfate [7]. Currently, there is no direct measurement that can be performed toassess tau aggregation in living organisms; however, brain imaging using singlephoton emission computed tomography scans is in development.

In general, efforts aimed at either preventing or reversing tau aggregation aremuch further advanced than those targeting chaperones. Tau contains awell-characterized, aggregation-prone peptide sequence in the third microtubulebinding repeat domain of exon 10+ tau. This hexapeptide motif, VQIVYK, locatedat amino acids 306 to 311, has been shown to exhibit the highest propensity toaggregate [8]. Drugs that directly bind near this hexapeptide region have been themost effective at preventing tau aggregation [9]. Interestingly, however this hexapeptide domain is also the regionthat chaperones most readily recognize [10]. This further suggests that there is some interplay between tauaggregation and its regulation by chaperones.

Heat shock proteins as therapeutic targets

Hsps are a group of molecular chaperones that assist in protein folding,transport, and degradation. These chaperones have been extensively studied fortheir ability to regulate aberrant intracellular proteins. Typically, misfoldedtau collects in the soma and accumulates in the somatodendritic compartment [11, 12]. Intracellular factors that can readily access this compartment aretherapeutic options for preventing tau aggregation or degrading aberrant tauspecies. Molecular chaperones are naturally able to maintain a gateway thatcould determine the fate of a non-native protein, such as aggregated tau;however, with aging, this system begins to slow and proteins unnaturallyaccumulate. This age-induced blockade can be caused by many factors, includingdysfunctional or decreased degradation mechanisms [13] or declining chaperone levels coupled with rising levels of misfoldedproteins [14].

The Hsp70, small Hsp, and Hsp90 families are notably known to play roles in taupathology [15, 16]. Currently, therapeutics targeting Hsp90 have shown promise as taureducing agents [17, 18]; however, a common problem with Hsp90 inhibitors is that theystimulate the transcription factor heat shock factor protein 1 (HSF1). Uponstress, HSF1 activation leads to induced expression of a whole panel of otherHsps that can antagonize the effects of Hsp90 inhibition. Hsp70 inhibitors havealso shown promise as anti-tau therapeutics [19], and they do not cause a heat shock induction. However, there aremore Hsp70 variants in the cell, each with different functions, and theseinhibitors are not selective for one over the other. This non-specificinhibition could lead to unwanted side effects. There is also a need to increaseblood–brain barrier (BBB) permeability of these compounds in order tocreate drugs that can be delivered peripherally yet treat centrally, a processthat is in development [20].

Hsp90 inhibition decreases tau

The Hsp90 chaperone is a highly conserved, ATP-requiring protein that functionsas part of a large protein complex. Among others, this complex includes theco-chaperones cell division control 37 kDa (Cdc37), FK506 binding protein 51 kDa(FKBP51), and carboxyl terminus of Hsc70-interacting protein (CHIP), all ofwhich contain tetratricopeptide repeat domains that allow Hsp90 binding and aidin directing Hsp90 function. Since the original discovery that Hsp90 inhibitorscould facilitate tau clearance [17, 18], many Hsp90 inhibitors have been identified as potential tautherapeutics. These inhibitors include radicicol and its multiple derivatives,geldanamycin, the geldanamycin analog 17-(allylamino)-17-demethoxygeldamycin(17-AAG), andN-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)acetamide(KU-32). (For a comprehensive review of Hsp90 inhibitors, see [21]).

Of these inhibitors, geldanamycin has been the most studied as a tau therapeutic.An Hsp90-inhibiting antibiotic used to cause alterations in tau, geldanamycinhas been shown to decrease levels of insoluble tau aggregates by 80% whileleaving total tau levels unchanged [22]. Recently, a group showed that geldanamycin was able to activate theproteasome to cause tau degradation [23], and another study showed in a primary neuron model that geldanamycintreatment led to decreased tau phosphorylation by downregulating aberrant kinaseactivity [24]. Geldanamycin inhibits the Hsp90 homodimer by binding to its twoN-terminal nucleotide binding domains [25]. However, geldanamycin proved to be quite toxic [26], prompting the development and testing of the geldanamycin analog17-AAG.

Recent developments of Hsp90 inhibitors

Compared with its parent molecule, 17-AAG showed lower toxicity and had morepotent effects at decreasing tau phosphorylation in primary neurons [24]. 17-AAG was also able to decrease tau in an in vitro modelof tauopathy [27]. Although the analog compound was unable to alter tau phosphorylationat serines 396 and 404 or rescue a motor deficit, Sinadinos and colleaguesrecently showed that treating Drosophila larvae expressing human 3R tau with17-AAG dramatically decreased total tau levels [28].

In addition to 17-AAG, radicicol is another Hsp90 inhibitor that was discoveredafter geldanamycin. Radicicol is a natural product that inhibits Hsp90 whileinducing Hsp40 and Hsp70. Again in a Drosophila model, radicicol has been shownto dose-dependently decrease the levels of tau [28]. Analogs of radicicol, originally made for use in oncogenic research,have yet to be evaluated for their effects on tau [29].

Owing to the potentially toxic effects of N-terminal Hsp90 ATPase inhibitors,C-terminal ATPase inhibitors are now thought to be preferred. These C-terminalinhibitors are currently in development through new research on novobiocininhibitors. Novobiocin is an antibiotic that binds to the two C-terminal ATPasesites of the Hsp90 homodimer. Analogues of novobiocin were developed by theBlagg group to test whether C-terminal ATPase inhibition of Hsp90 would yieldfewer toxic side effects. From these studies, the new lead compound KU-32 showedthe greatest potential for efficacy against diseases of the central nervoussystem because it could cross the BBB, and caused an attenuated heat shockresponse compared with N-terminal inhibitors [30, 31]. The effects of KU-32 on tau biology in vivo have not yetbeen evaluated, but it appears to be a promising drug candidate fortauopathies.

Because inhibition of Hsp90 in many cases activates HSF1, it is very difficult toelucidate the mechanism by which Hsp90 inhibition decreases tau levels oraggregates. Additionally, as Hsp90 is involved in many diseases and isubiquitously expressed, striving for one specific result through global Hsp90inhibition may lead to many off-target effects. More effort has been placedrecently on developing drugs that target co-chaperones of Hsp90 for increasedspecificity. This development, however, is in its infancy. Withaferin A, oneknown inhibitor of the Hsp90 co-chaperone Cdc37, was shown to decreaseaggregated tau in a mouse model, but it also led to the induction of Hsp27 andHsp70 [28]. Other Hsp90 co-chaperones, such as FKBP51 [32] and CHIP [22], have been identified as being good targets for altering tauphosphorylation states and levels. However, compounds directed at these targetshave yet to be developed.

Targeting Hsp70 with small molecules

Along with the Hsp90 family, Hsp70 has been extensively studied as a therapeutictarget for modulating tau [15, 22, 33]. The Hsp70 family is a ubiquitously expressed group that can preventprotein aggregation through ATP hydrolyses [34]. This family includes more than 10 members. The most commonly studiedare the constitutively expressed Hsp73 (heat shock cognate (Hsc)70), the stressinduced Hsp72 (Hsp70), glucose-regulated protein (GRP)78 (BiP), which isexpressed in the endoplasmic reticulum, and mitochondrial GRP75 (mortalin) [35]. These ~70 kDa proteins have three functional domains: an N-terminalATPase domain, a substrate binding domain, and a C-terminal domain thatfunctions as a lid.

Although many of the Hsp90 inhibitors discussed above can be also included in theHsp70 modulating category because they induce Hsp70 expression, recent work fromour group and others have identified Hsp70-specific modulating drugs that canpotently facilitate tau clearance [20, 33, 36]. Both activators and inhibitors of Hsp70 ATPase function have beenidentified, and these compounds appear to regulate the association of Hsp70proteins with either DnaJ/Hsp40 proteins or nucleotide exchange factors, whichin turn alters the ATPase activity of Hsp70. Currently, these compounds arederived from three drug families; the flavonoids, the phenothiazine dyes, andthe rhodocyanine dyes [37, 38]. Importantly, these compounds have few known side effects. AlteringATPase function has been shown to affect tau biology, so these Hsp70 ATPasemodulators may be relevant targets for tauopathies.

Flavonoids as anti-tau therapeutics

Natural products research has yielded many unique, active compounds. A class ofthese known as flavonoids have had broad implications in many diseases. Whilethe flavonoid myricetin possesses anti-Hsp70 activity and reduces tau levels [33], other flavonoids that lack anti-Hsp70 activity can still reduce taulevels, including curcumin [39] and quercetin [40]. Curcumin has been shown to alter tau phosphorylation in primaryneurons [41]. Moreover, this yellow compound has recently been implicated to havetherapeutic value in mouse models of tauopathies [42]. Just last year, curcumin was shown to elevate Hsp90 and Hsc70without affecting HSF1, while suppressing soluble tau but not insoluble tau [43]. Moreover, curcumin is BBB permeable and showed a significantbehavioral deficit rescue. Curcumin has been involved with many clinical trialsand is well tolerated, but its efficacy in the treatment or prevention oftauopathies has yet to be clearly demonstrated. Quercetin has shown protectiveeffects against amyloid-beta pathology and may have a therapeutic role for tauaggregation.

Phenothiazines: efficacy through pleiotropy

Phenothiazines have been studied for their therapeutic potential for over acentury. One phenothiazine, methylene blue (MB; phenothiazine methylthioniumchloride), has been involved in multiple clinical trials testing its efficacyfor many diseases ranging from psychiatric disorders to cancer [44]. In addition, MB was originally identified as a potent beta-pleatedsheet inhibitor [45] and more recently as an Hsp70 inhibitor [33].

Regardless of the mechanism, MB has been shown to be protective against tauaccumulation in several models. Specifically, our group showed that MB givenad libitum in drinking water or through osmotic pump into the braindecreased tau phosphorylation and rescued learning impairment in rTg4510 mice [46]. This has since been validated by several other groups [37, 47, 48]. Another group showed that MB treatment on a tau C. elegansmodel alleviated tau-induced neuronal toxicity [49]. A proprietary formulation of MB has successfully passed throughphase 1 and phase 2 clinical trials according to reports from TauRx Therapeutics(Singapore, Republic of Singapore) [50]. This year, the drug will go into phase 3 trials, for which patientsare currently being recruited. The study is scheduled to conclude in 2015 [51].

Although MB is progressing in the clinic and has low toxicity, there are somedrawbacks of this drug. MB is blue in color and causes discoloration of the eyesand urine; occasionally, it can also induce nausea.

Another member of the phenothiazine family, quinoxalines have a structure similarto MB. These compounds have been shown to have potent activity in preventing andeven reversing the aggregation of tau. However, quinoxalines, while able topermeate the BBB, were found to have very low absorption in vivo,making them inadequate as possible therapeutics for tau aggregation [39].

Rhodocyanines: a promising Hsp70 inhibitor scaffold

Rhodocyanine dyes have been studied for over a century for their therapeuticpotential. Recent work from our group shows that one example of these dyes,1-ethyl-2-((3-ethyl-5-(3-methylbenzothiazolin-2-yliden))-4-oxothiazolidin-2-ylidenemethyl)pyridinium chloride (MKT-077), can inhibit Hsp70 ATPase activity and facilitatetau clearance [36, 52, 53]. Researchers have been working to alter the chemical structure ofMKT-077 to increase its potency, BBB permeability and target specificity, and toreduce its off-target effects [20, 54].

A new family of MKT-077 compounds has been created, including the recentlypublished YM compounds [20]. Two of these analogs, YM-01 and YM-08, showed anti-tau activity.Compared with the mostly mitochondrial MKT-077, YM-01 is more concentrated inthe cytosol – potentially allowing it to be more accessible to cytosolicHsp70 [54], conferring improved anti-tau efficacy. YM-08 is a further refinementof YM-01 that has reduced potency but dramatically improved BBB permeability [20].

Small heat shock proteins: no enzymatic activity, yet major functionality

Small Hsps are ATP-independent molecular chaperones with a molecular mass under43 kDa. The small Hsps have two primary domains, one of which is an alphacrystalline C-terminal domain. These small Hsps are known to self-dimerize andoligomerize [55]. Upon a stress event, they become phosphorylated and dissociate toact upon non-native proteins [56].

Our group and others have shown that Hsp27 has relevant therapeutic potential.In vitro, Hsp27 was able to prevent the aggregation of taufilaments, as measured by dynamic light scattering and atomic force microscopy.Hsp27 is also able to prevent tau accumulation and rescue long-term potentiationdeficits [16, 36].

Hsp22 and Hsp25 have not been extensively explored for their effects on tauaggregation. However, they have been shown to prevent other amyloid accumulationsuch as amyloid-beta [57] and alpha-synuclein [58] aggregation. While compounds that regulate the activity of thesesmall Hsps are not yet available, it is possible that they may be useful astherapeutics in recombinant form or via gene delivery. This is a developing areathat could hold great promise for tauopathies.

Small molecule inhibitors of tau aggregation

While chaperone modulation of tau is an emerging field, preventing tauaggregation directly with compounds that bind tau is much further developed.Rhodanine drugs, including epalrestat and troglitazone, have been extensivelydeveloped and characterized by the Mandelkow group for their ability to altertau aggregation. These low-toxicity compounds are actually able to disaggregateinsoluble tau fibrils, known as paired helical filament tau [39]. This group performed an extensive characterization of over 50derivatives, several of which proved to be potent compounds that prevented tauaggregation in neuronal cell lines [38]. Further developments of highly membrane permeable analogs arenecessary to test these drugs in vivo.

Anthraquinones are synthetic, organic compounds that can also potently preventand reverse tau aggregation [59]. A few derivatives that have exhibited anti-amyloidogenic propertiesinclude emodin, daunorubicin, mitoxantrone, and pixantrone [60]. Recently, the nontoxic analog anthraquinone-2-sulfonic acid (AQ2S)was identified to have not only anti-aggregation properties but was also foundto be neuroprotective [61, 62]. The structurally similar N-phenylamine also possessesanti-amyloidogenic properties. Derivatives of this compound, B1C11, B4D3, B4A1,and B4D5, have been shown to not only significantly prevent tau polymerization,but also to disassemble tau fibrils with relatively low toxicity [60]. However, there are no data that display the efficacy of these drugsin vivo.

Another aromatic scaffold, phenylthiazolyl-hydrazide was identified from a drugscreen as a tau aggregation inhibitor. In one screen, thephenylthiazolyl-hydrazide derivative BSc3094 was identified to most effectivelyprevent and reverse tau aggregation out of dozens of phenylthiazolyl-hydrazideanalogs produced, many of which showed some anti-amyloid activity. This familyhas low toxicity and their activity was also shown to be cytoprotective in aneuronal cell model of tauopathy [63].

Natural products have not only been shown to effect tau through chaperonemodulation, as described above, but also through direct interaction with tau.Oleuropein, hydroxytyrosol, and oleuropein aglycone were isolated from oliveextraction and showed anti-tau aggregation efficacy, with oleuropein having thegreatest potency [5]. Future in vivo studies are needed to look at efficacy inthe brain. Data suggest that oleuropein cannot pass the BBB, but the aglyconeanalog has remained untested. Treatment of hydroxytyrosol, which is BBBpermeable, in an in vivo tau mouse model would be necessary todetermine aggregation inhibitory activity in the brain. Important to note isthat administration of some phenols extracted from foods have been shown toexhibit different activity than that predicted in vivo[64].

Members in the carbocyanine scaffold, a group of blue–green dyes, have beenshown to block tau aggregation; however, the potency of these drugs is variable.The structural composition of the linker chains in bis-thiacarbocyaninederivatives was recently shown to lead to changes in the efficacy of aggregationinhibition [65]. One small molecule inhibitor in this family,3,3′-bis(β-hydroxyethyl)-9-ethyl-5,5′-dimethoxythiacarbocyanineiodide (N744), has been shown to have biphasic effects on tau aggregation [66]. This is not a surprising result, since other dye-based inhibitorsare effective at preventing tau polymerization at specific concentrations, andnot dose dependently [67]. N744 has additionally been shown to disaggregate tau filaments in arecombinant system [66]. Other analogs in this family, such as3,3′-diethyl-9-methyl-thiacarbocyanine iodide (C11), exhibited inhibitoryaggregate activity in ex vivo tissue slices from a mouse lineexpressing human tau [68].

A new small molecule, 2,6-diamino-3,5-dithiocyanopyridine, thiocyanic acidC,C′-(2,6-diamino-3,5-pyridinediyl) ester,2,6-diaminopyridine-3,5-bis(thiocyanate) (PR-619), is an inhibitor of ubiquitinisopeptidases that upregulate Hsp70. An in vitro system showed thatPR-619 was able to stabilize the microtubule network [69]. This same study showed that treatment led to small tau aggregatessurrounding the microtubule organizing center. Importantly, tau phosphorylationat both serines 396 and 404 and serines 262 and 356 (12E8) was decreased, whichincreased the ability of tau to bind the microtubules [69]. Translation of this drug to an in vivo rodent model wouldbe important to understand its therapeutic potential.

Conclusion

Tau aggregation contributes to the pathogenesis of many neurodegenerative diseases.Finding therapeutics that can prevent or reverse this non-native accumulation isthus highly desirable. Although many compounds have been recently identified to haveanti-aggregative effects on tau, the large majority of these small moleculeinhibitors is not specific for tau aggregates, but rather targets all proteins thatcan form beta-sheet amyloids. This lack of specificity may alter pharmacodynamicsbetween individuals, making the appropriate dose difficult to assess based on thetotal amyloid burden in the body. The macrocyclic drugs are the first to besynthetically designed to specifically bind tau [9]. Further development of these compounds may help identify a tau specificinhibitor that is active in vivo.

Currently many aggregation inhibitors would need to be used at high concentrations tobe effective against the high levels of tau present in neurons [70]. Tau is typically found in axons, but is thought to be furtherconcentrated into somatodendritic aggregates in disease [71]. Delivering aggregation inhibitors with assistance from nanoparticleencapsulation [72] could therefore boost their efficacy by increasing their concentration inthe brain. Other strategies that preferentially and specifically target tauaggregates within neurons or areas within the neuron where tau aggregates arepresent could also increase the potential for success. Perhaps combining therapiesthat specifically target tau aggregates and then facilitate tau clearance wouldfurther overcome this potential problem associated with high focal concentrations oftau.

The combination of tau aggregation inhibitors with compounds that can facilitate tauclearance could be advantageous in a clinical setting, possibly producing truesynergy. Molecular chaperones are a prime target for regulating tau turnover; manydrugs have been identified that alter the expression or activities of chaperoneproteins, and advances in the last decade have increased drug efficacy and BBBpermeability. These developments have allowed us to advance our understanding of therole of tau accumulation in disease, but concerns about specificity and off-targeteffects have slowed the progress of these compounds to the clinic. In addition,drugs that prevent aggregation, disaggregation, degradation, or increased expressionmay not be effective in preventing or reversing tauopathy phenotypes. Constructingthe next generation of small molecule drugs to selectively eliminate only abnormaltau may be essential, a strategy that may now be possible given our advancedunderstanding of tau triage biology.

Note

This article is part of the series on Tau-based therapeutic strategies,edited by Leonard Petrucelli. Other articles in this series can be found athttp://alzres.com/series/tau_therapeutics

Abbreviations

17-AAG:

17-(allylamino)-17-demethoxygeldamycin

AQ2S:

Anthraquinone-2-sulfonic acid

BBB:

Blood–brain barrier

C11:

3,3′-diethyl-9-methyl-thiacarbocyanineiodide

Cdc37:

Cell division control 37 kDa

CHIP:

Carboxyl terminus ofHsc70-interacting protein

FKBP51:

FK506 binding protein 51 kDa

GRP:

Glucose-regulated protein

HSF1:

Heat shock factor protein 1

Hsc:

Heat shockcognate

Hsp:

Heat shock protein

KU-32:

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)acetamide

MB:

Methylene blue (phenothiazine methylthionium chloride)

MKT-077:

1-ethyl-2-((3-ethyl-5-(3-methylbenzothiazolin-2-yliden))-4-oxothiazolidin-2-ylidenemethyl)pyridinium chloride

N744:

3,3′-bis(β-hydroxyethyl)-9-ethyl-5,5′-dimethoxythiacarbocyanineiodide

PR619:

2,6-diamino-3,5-dithiocyanopyridine, thiocyanic acidC,C′-(2,6-diamino-3,5-pyridinediyl) ester,2,6-diaminopyridine-3,5-bis(thiocyanate).

References

  1. Hardy J, Orr H: The genetics of neurodegenerative diseases. J Neurochem. 2006, 97: 1690-1699. 10.1111/j.1471-4159.2006.03979.x.

    Article  CAS  PubMed  Google Scholar 

  2. Abisambra JF, Blair LJ, Hill SE, Jones J, Kraft C, Rogers J, Koren J, Jinwal UK, Lawson LY, Johnson AG, Wilcock D, O'Leary JC, Jansen-West K, Muschol M, Golde TE, Weeber EJ, Banko J, Dickey CA: Phosphorylation dynamics regulate Hsp27-mediated rescue of neuronalplasticity deficits in tau transgenic mice. J Neurosci. 2010, 30: 15374-15382. 10.1523/JNEUROSCI.3155-10.2010.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Voss K, Combs B, Patterson KR, Binder LI, Gamblin TC: Hsp70 alters tau function and aggregation in an isoform specific manner. Biochemistry. 2012, 51: 888-898. 10.1021/bi2018078.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Thompson AD, Scaglione KM, Prensner J, Gillies AT, Chinnaiyan A, Paulson HL, Jinwal UK, Dickey CA, Gestwicki JE: Analysis of the tau-associated proteome reveals that exchange of Hsp70 forHsp90 is involved in tau degradation. ACS Chem Biol. 2012, 7: 1677-1686. 10.1021/cb3002599.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Daccache A, Lion C, Sibille N, Gerard M, Slomianny C, Lippens G, Cotelle P: Oleuropein and derivatives from olives as Tau aggregation inhibitors. Neurochem Int. 2011, 58: 700-707. 10.1016/j.neuint.2011.02.010.

    Article  CAS  PubMed  Google Scholar 

  6. Chang E, Congdon EE, Honson NS, Duff KE, Kuret J: Structure–activity relationship of cyanine tau aggregationinhibitors. J Med Chem. 2009, 52: 3539-3547. 10.1021/jm900116d.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Khlistunova I, Biernat J, Wang Y, Pickhardt M, von Bergen M, Gazova Z, Mandelkow E, Mandelkow EM: Inducible expression of Tau repeat domain in cell models of tauopathy:aggregation is toxic to cells but can be reversed by inhibitor drugs. J Biol Chem. 2006, 281: 1205-1214.

    Article  CAS  PubMed  Google Scholar 

  8. Bulic B, Pickhardt M, Schmidt B, Mandelkow EM, Waldmann H, Mandelkow E: Development of tau aggregation inhibitors for Alzheimer's disease. Angew Chem. 2009, 48: 1740-1752. 10.1002/anie.200802621.

    Article  CAS  Google Scholar 

  9. Zheng J, Liu C, Sawaya MR, Vadla B, Khan S, Woods RJ, Eisenberg D, Goux WJ, Nowick JS: Macrocyclic beta-sheet peptides that inhibit the aggregation of atau-protein-derived hexapeptide. J Am Chem Soc. 2011, 133: 3144-3157. 10.1021/ja110545h.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Jinwal UK, Akoury E, Abisambra JF, O'Leary JC, Thompson AD, Blair LJ, Jin Y, Bacon J, Nordhues BA, Cockman M, Zhang J, Li P, Zhang B, Borysov S, Uversky VN, Biernat J, Mandelkow E, Gestwicki JE, Zweckstetter M, Dickey CA: Imbalance of Hsp70 family variants fosters tau accumulation. FASEB J. 2013, 27: 1450-1459. 10.1096/fj.12-220889.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Wolozin BL, Pruchnicki A, Dickson DW, Davies P: A neuronal antigen in the brains of Alzheimer patients. Science. 1986, 232: 648-650. 10.1126/science.3083509.

    Article  CAS  PubMed  Google Scholar 

  12. Wood JG, Mirra SS, Pollock NJ, Binder LI: Neurofibrillary tangles of Alzheimer disease share antigenic determinantswith the axonal microtubule-associated protein tau (tau). Proc Natl Acad Sci U S A. 1986, 83: 4040-4043. 10.1073/pnas.83.11.4040.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Massey AC, Zhang C, Cuervo AM: Chaperone-mediated autophagy in aging and disease. Curr Top Dev Biol. 2006, 73: 205-235.

    Article  CAS  PubMed  Google Scholar 

  14. Dickey C, Kraft C, Jinwal U, Koren J, Johnson A, Anderson L, Lebson L, Lee D, Dickson D, de Silva R, Binder LI, Morgan D, Lewis J: Aging analysis reveals slowed tau turnover and enhanced stress response in amouse model of tauopathy. Am J Pathol. 2009, 174: 228-238. 10.2353/ajpath.2009.080764.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Dou F, Netzer WJ, Tanemura K, Li F, Hartl FU, Takashima A, Gouras GK, Greengard P, Xu H: Chaperones increase association of tau protein with microtubules. Proc Natl Acad Sci U S A. 2003, 100: 721-726. 10.1073/pnas.242720499.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Shimura H, Miura-Shimura Y, Kosik KS: Binding of tau to heat shock protein 27 leads to decreased concentration ofhyperphosphorylated tau and enhanced cell survival. J Biol Chem. 2004, 279: 17957-17962. 10.1074/jbc.M400351200.

    Article  CAS  PubMed  Google Scholar 

  17. Dickey CA, Kamal A, Lundgren K, Klosak N, Bailey RM, Dunmore J, Ash P, Shoraka S, Zlatkovic J, Eckman CB, Patterson C, Dickson DW, Nahman NS, Hutton M, Burrows F, Petrucelli L: The high-affinity HSP90-CHIP complex recognizes and selectively degradesphosphorylated tau client proteins. J Clin Invest. 2007, 117: 648-658. 10.1172/JCI29715.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Luo W, Dou F, Rodina A, Chip S, Kim J, Zhao Q, Moulick K, Aguirre J, Wu N, Greengard P, Chiosis G: Roles of heat-shock protein 90 in maintaining and facilitating theneurodegenerative phenotype in tauopathies. Proc Natl Acad Sci U S A. 2007, 104: 9511-9516. 10.1073/pnas.0701055104.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Jinwal UK, Koren J, O'Leary JC, Jones JR, Abisambra JF, Dickey CA: Hsp70 ATPase modulators as therapeutics for Alzheimer's and otherneurodegenerative diseases. Mol Cell Pharmacol. 2010, 2: 43-46.

    PubMed Central  CAS  PubMed  Google Scholar 

  20. Miyata Y, Li X, Lee H-F, Jinwal UK, Srinivasan SR, Seguin SP, Young ZT, Brodsky JL, Dickey CA, Sun D, Gestwicki JE: Synthesis and initial evaluation of YM-08, a blood–brain barrierpermeable derivative of the heat shock protein 70 (Hsp70) inhibitor MKT-077,which reduces tau levels. ACS Chem Neurosci. 2013, 4: 930-939. 10.1021/cn300210g.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Zhao H, Michaelis ML, Blagg BS: Hsp90 modulation for the treatment of Alzheimer's disease. Adv Pharmacol. 2012, 64: 1-25.

    Article  CAS  PubMed  Google Scholar 

  22. Petrucelli L, Dickson D, Kehoe K, Taylor J, Snyder H, Grover A, De Lucia M, McGowan E, Lewis J, Prihar G, Kim J, Dillmann WH, Browne SE, Hall A, Voellmy R, Tsuboi Y, Dawson TM, Wolozin B, Hardy J, Hutton M: CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum Mol Genet. 2004, 13: 703-714. 10.1093/hmg/ddh083.

    Article  CAS  PubMed  Google Scholar 

  23. Opattova A, Filipcik P, Cente M, Novak M: Intracellular degradation of misfolded tau protein induced by geldanamycin isassociated with activation of proteasome. J Alzheimers Dis. 2013, 33: 339-348.

    CAS  PubMed  Google Scholar 

  24. Dou F, Yuan LD, Zhu JJ: Heat shock protein 90 indirectly regulates ERK activity by affecting Rafprotein metabolism. Acta Biochim Biophys Sin. 2005, 37: 501-505. 10.1111/j.1745-7270.2005.00069.x.

    Article  CAS  PubMed  Google Scholar 

  25. Grenert JP, Sullivan WP, Fadden P, Haystead TA, Clark J, Mimnaugh E, Krutzsch H, Ochel HJ, Schulte TW, Sausville E, Neckers LM, Toft DO: The amino-terminal domain of heat shock protein 90 (hsp90) that bindsgeldanamycin is an ATP/ADP switch domain that regulates hsp90conformation. J Biol Chem. 1997, 272: 23843-23850. 10.1074/jbc.272.38.23843.

    Article  CAS  PubMed  Google Scholar 

  26. Ansar S, Burlison JA, Hadden MK, Yu XM, Desino KE, Bean J, Neckers L, Audus KL, Michaelis ML, Blagg BS: A non-toxic Hsp90 inhibitor protects neurons from Abeta-induced toxicity. Bioorg Med Chem Lett. 2007, 17: 1984-1990. 10.1016/j.bmcl.2007.01.017.

    Article  CAS  PubMed  Google Scholar 

  27. Dickey CA, Koren J, Zhang YJ, Xu YF, Jinwal UK, Birnbaum MJ, Monks B, Sun M, Cheng JQ, Patterson C, Bailey RM, Dunmore J, Soresh S, Leon C, Morgan D, Petrucelli L: Akt and CHIP coregulate tau degradation through coordinated interactions. Proc Natl Acad Sci U S A. 2008, 105: 3622-3627. 10.1073/pnas.0709180105.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Sinadinos C, Quraishe S, Sealey M, Samson PB, Mudher A, Wyttenbach A: Low endogenous and chemical induced heat shock protein induction in a0N3Rtau-expressing Drosophila larval model of Alzheimer's disease. J Alzheimers Dis. 2013, 33: 1117-1133.

    CAS  PubMed  Google Scholar 

  29. Soga S, Shiotsu Y, Akinaga S, Sharma SV: Development of radicicol analogues. Curr Cancer Drug Targets. 2003, 3: 359-369. 10.2174/1568009033481859.

    Article  CAS  PubMed  Google Scholar 

  30. Li C, Ma J, Zhao H, Blagg BS, Dobrowsky RT: Induction of heat shock protein 70 (Hsp70) prevents neuregulin-induceddemyelination by enhancing the proteasomal clearance of c-Jun. ASN Neuro. 2012, 4: e00102-

    Article  PubMed Central  PubMed  Google Scholar 

  31. Lu Y, Ansar S, Michaelis ML, Blagg BS: Neuroprotective activity and evaluation of Hsp90 inhibitors in animmortalized neuronal cell line. Bioorg Med Chem. 2009, 17: 1709-1715. 10.1016/j.bmc.2008.12.047.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Jinwal UK, Koren J, Borysov SI, Schmid AB, Abisambra JF, Blair LJ, Johnson AG, Jones JR, Shults CL, O'Leary JC, Jin Y, Buchner J, Cox MB, Dickey CA: The Hsp90 cochaperone, FKBP51, increases Tau stability and polymerizesmicrotubules. J Neurosci. 2010, 30: 591-599. 10.1523/JNEUROSCI.4815-09.2010.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Jinwal UK, Miyata Y, Koren J, Jones JR, Trotter JH, Chang L, O'Leary J, Morgan D, Lee DC, Shults CL, Rousaki A, Weeber EJ, Zuiderweg ER, Gestwicki JE, Dickey CA: Chemical manipulation of hsp70 ATPase activity regulates tau stability. J Neurosci. 2009, 29: 12079-12088. 10.1523/JNEUROSCI.3345-09.2009.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Wisen S, Gestwicki JE: Identification of small molecules that modify the protein folding activity ofheat shock protein 70. Anal Biochem. 2008, 374: 371-377. 10.1016/j.ab.2007.12.009.

    Article  CAS  PubMed  Google Scholar 

  35. Zuiderweg ER, Bertelsen EB, Rousaki A, Mayer MP, Gestwicki JE, Ahmad A: Allostery in the Hsp70 chaperone proteins. Top Curr Chem. 2013, 328: 99-153.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Abisambra J, Jinwal UK, Miyata Y, Rogers J, Blair L, Li X, Seguin SP, Wang L, Jin Y, Bacon J, Brady S, Cockman M, Guidi C, Zhang J, Koren J, Young ZT, Atkins CA, Zhang B, Lawson LY, Weeber EJ, Brodsky JL, Gestwicki JE, Dickey CA: Allosteric heat shock protein 70 inhibitors rapidly rescue synapticplasticity deficits by reducing aberrant tau. Biol Psychiatry. 2013, 74: 367-374. 10.1016/j.biopsych.2013.02.027.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Akoury E, Pickhardt M, Gajda M, Biernat J, Mandelkow E, Zweckstetter M: Mechanistic basis of phenothiazine-driven inhibition of tau aggregation. Angew Chem. 2013, 52: 3511-3515. 10.1002/anie.201208290.

    Article  CAS  Google Scholar 

  38. Bulic B, Pickhardt M, Khlistunova I, Biernat J, Mandelkow EM, Mandelkow E, Waldmann H: Rhodanine-based tau aggregation inhibitors in cell models of tauopathy. Angew Chem. 2007, 46: 9215-9219. 10.1002/anie.200704051.

    Article  Google Scholar 

  39. Bulic B, Pickhardt M, Mandelkow EM, Mandelkow E: Tau protein and tau aggregation inhibitors. Neuropharmacology. 2010, 59: 276-289. 10.1016/j.neuropharm.2010.01.016.

    Article  CAS  PubMed  Google Scholar 

  40. Lu J, Wu DM, Zheng YL, Hu B, Zhang ZF, Shan Q, Zheng ZH, Liu CM, Wang YJ: Quercetin activates AMP-activated protein kinase by reducing PP2C expressionprotecting old mouse brain against high cholesterol-inducedneurotoxicity. J Pathol. 2010, 222: 199-212. 10.1002/path.2754.

    Article  CAS  PubMed  Google Scholar 

  41. Narlawar R, Pickhardt M, Leuchtenberger S, Baumann K, Krause S, Dyrks T, Weggen S, Mandelkow E, Schmidt B: Curcumin-derived pyrazoles and isoxazoles: Swiss army knives or blunt toolsfor Alzheimer's disease?. ChemMedChem. 2008, 3: 165-172. 10.1002/cmdc.200700218.

    Article  CAS  PubMed  Google Scholar 

  42. Ma QL, Yang F, Rosario ER, Ubeda OJ, Beech W, Gant DJ, Chen PP, Hudspeth B, Chen C, Zhao Y, Vinters HV, Frautschy SA, Cole GM: Beta-amyloid oligomers induce phosphorylation of tau and inactivation ofinsulin receptor substrate via c-Jun N-terminal kinase signaling:suppression by omega-3 fatty acids and curcumin. J Neurosci. 2009, 29: 9078-9089. 10.1523/JNEUROSCI.1071-09.2009.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Ma QL, Zuo X, Yang F, Ubeda OJ, Gant DJ, Alaverdyan M, Teng E, Hu S, Chen PP, Maiti P, Teter B, Cole GM, Frautschy SA: Curcumin suppresses soluble tau dimers and corrects molecular chaperone,synaptic, and behavioral deficits in aged human tau transgenic mice. J Biol Chem. 2013, 288: 4056-4065. 10.1074/jbc.M112.393751.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Schirmer RH, Adler H, Pickhardt M, Mandelkow E: ‘Lest we forget you – methylene blue... Neurobiol Aging. 2011, 32 (2325): e7-e16.

    PubMed  Google Scholar 

  45. Wischik CM, Edwards PC, Lai RY, Roth M, Harrington CR: Selective inhibition of Alzheimer disease-like tau aggregation byphenothiazines. Proc Natl Acad Sci U S A. 1996, 93: 11213-11218. 10.1073/pnas.93.20.11213.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. O'Leary JC, Li Q, Marinec P, Blair LJ, Congdon EE, Johnson AG, Jinwal UK, Koren J, Jones JR, Kraft C, Peters M, Abisambra JF, Duff KE, Weeber EJ, Gestwicki JE, Dickey CA: Phenothiazine-mediated rescue of cognition in tau transgenic mice requiresneuroprotection and reduced soluble tau burden. Mol Neurodegener. 2010, 5: 45-10.1186/1750-1326-5-45.

    Article  PubMed Central  PubMed  Google Scholar 

  47. Congdon EE, Wu JW, Myeku N, Figueroa YH, Herman M, Marinec PS, Gestwicki JE, Dickey CA, Yu WH, Duff KE: Methylthioninium chloride (methylene blue) induces autophagy and attenuatestauopathy in vitro and in vivo. Autophagy. 2012, 8: 609-622. 10.4161/auto.19048.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Brunden KR, Trojanowski JQ, Lee VM: Advances in tau-focused drug discovery for Alzheimer's disease and relatedtauopathies. Nat Rev Drug Discov. 2009, 8: 783-793. 10.1038/nrd2959.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Fatouros C, Pir GJ, Biernat J, Koushika SP, Mandelkow E, Mandelkow EM, Schmidt E, Baumeister R: Inhibition of tau aggregation in a novel Caenorhabditis elegans model oftauopathy mitigates proteotoxicity. Hum Mol Genet. 2012, 21: 3587-3603. 10.1093/hmg/dds190.

    Article  CAS  PubMed  Google Scholar 

  50. Wischik C, Staff R: Challenges in the conduct of disease-modifying trials in AD: practicalexperience from a phase 2 trial of Tau-aggregation inhibitor therapy. J Nutr Health Aging. 2009, 13: 367-369. 10.1007/s12603-009-0046-5.

    Article  CAS  PubMed  Google Scholar 

  51. Safety and efficacy study evaluating TRx0237 in subjects with mild tomoderate alzheimer’s disease.http://www.clinicaltrials.gov/ct2/show/NCT01689246?term=alzheimer%27s&rank=10,

  52. Miyata Y, Koren J, Kiray J, Dickey CA, Gestwicki JE: Molecular chaperones and regulation of tau quality control: strategies fordrug discovery in tauopathies. Future Med Chem. 2011, 3: 1523-1537. 10.4155/fmc.11.88.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Rousaki A, Miyata Y, Jinwal UK, Dickey CA, Gestwicki JE, Zuiderweg ER: Allosteric drugs: the interaction of antitumor compound MKT-077 with humanHsp70 chaperones. J Mol Biol. 2011, 411: 614-632. 10.1016/j.jmb.2011.06.003.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Koren J, Miyata Y, Kiray J, O'Leary JC, Nguyen L, Guo J, Blair LJ, Li X, Jinwal UK, Cheng JQ, Gestwicki JE, Dickey CA: Rhodacyanine derivative selectively targets cancer cells and overcomestamoxifen resistance. PLoS One. 2012, 7: e35566-10.1371/journal.pone.0035566.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Lelj-Garolla B, Mauk AG: Self-association of a small heat shock protein. J Mol Biol. 2005, 345: 631-642. 10.1016/j.jmb.2004.10.056.

    Article  CAS  PubMed  Google Scholar 

  56. Koteiche HA, McHaourab HS: Mechanism of chaperone function in small heat-shock proteins.Phosphorylation-induced activation of two-mode binding inalphaB-crystallin. J Biol Chem. 2003, 278: 10361-10367. 10.1074/jbc.M211851200.

    Article  CAS  PubMed  Google Scholar 

  57. Wilhelmus MM, de Waal RM, Verbeek MM: Heat shock proteins and amateur chaperones in amyloid-beta accumulation andclearance in Alzheimer's disease. Mol Neurobiol. 2007, 35: 203-216. 10.1007/s12035-007-0029-7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Bruinsma IB, Bruggink KA, Kinast K, Versleijen AA, Segers-Nolten IM, Subramaniam V, Bea Kuiperij H, Boelens W, de Waal RM, Verbeek MM: Inhibition of alpha-synuclein aggregation by small heat shock proteins. Proteins. 2011, 79: 2956-2967. 10.1002/prot.23152.

    Article  CAS  PubMed  Google Scholar 

  59. Jackson TC, Verrier JD, Kochanek PM: Anthraquinone-2-sulfonic acid (AQ2S) is a novel neurotherapeutic agent. Cell Death Dis. 2013, 4: e451-10.1038/cddis.2012.187.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Pickhardt M, Biernat J, Khlistunova I, Wang YP, Gazova Z, Mandelkow EM, Mandelkow E: N-phenylamine derivatives as aggregation inhibitors in cell models oftauopathy. Curr Alzheimer Res. 2007, 4: 397-402. 10.2174/156720507781788765.

    Article  CAS  PubMed  Google Scholar 

  61. Pickhardt M, Gazova Z, von Bergen M, Khlistunova I, Wang Y, Hascher A, Mandelkow EM, Biernat J, Mandelkow E: Anthraquinones inhibit tau aggregation and dissolve Alzheimer's pairedhelical filaments in vitro and in cells. J Biol Chem. 2005, 280: 3628-3635.

    Article  CAS  PubMed  Google Scholar 

  62. Convertino M, Pellarin R, Catto M, Carotti A, Caflisch A: 9,10-Anthraquinone hinders beta-aggregation: how does a small moleculeinterfere with Abeta-peptide amyloid fibrillation?. Protein Sci. 2009, 18: 792-800.

    PubMed Central  CAS  PubMed  Google Scholar 

  63. Pickhardt M, Larbig G, Khlistunova I, Coksezen A, Meyer B, Mandelkow EM, Schmidt B, Mandelkow E: Phenylthiazolyl-hydrazide and its derivatives are potent inhibitors of tauaggregation and toxicity in vitro and in cells. Biochemistry. 2007, 46: 10016-10023. 10.1021/bi700878g.

    Article  CAS  PubMed  Google Scholar 

  64. Acin S, Navarro MA, Arbones-Mainar JM, Guillen N, Sarria AJ, Carnicer R, Surra JC, Orman I, Segovia JC, Torre Rde L, Covas MI, Fernández-Bolaños J, Ruiz-Gutiérrez V, Osada J: Hydroxytyrosol administration enhances atherosclerotic lesion development inapo E deficient mice. J Biochem. 2006, 140: 383-391. 10.1093/jb/mvj166.

    Article  CAS  PubMed  Google Scholar 

  65. Schafer KN, Murale DP, Kim K, Cisek K, Kuret J, Churchill DG: Structure–activity relationship of cyclic thiacarbocyanine tauaggregation inhibitors. Bioorg Med Chem Lett. 2011, 21: 3273-3276. 10.1016/j.bmcl.2011.04.039.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Necula M, Chirita CN, Kuret J: Cyanine dye N744 inhibits tau fibrillization by blocking filament extension:implications for the treatment of tauopathic neurodegenerative diseases. Biochemistry. 2005, 44: 10227-10237. 10.1021/bi050387o.

    Article  CAS  PubMed  Google Scholar 

  67. Congdon EE, Necula M, Blackstone RD, Kuret J: Potency of a tau fibrillization inhibitor is influenced by its aggregationstate. Arch Biochem Biophys. 2007, 465: 127-135. 10.1016/j.abb.2007.05.004.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Congdon EE, Figueroa YH, Wang L, Toneva G, Chang E, Kuret J, Conrad C, Duff KE: Inhibition of tau polymerization with a cyanine dye in two distinct modelsystems. J Biol Chem. 2009, 284: 20830-20839. 10.1074/jbc.M109.016089.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  69. Seiberlich V, Goldbaum O, Zhukareva V, Richter-Landsberg C: The small molecule inhibitor PR-619 of deubiquitinating enzymes affects themicrotubule network and causes protein aggregate formation in neural cells:implications for neurodegenerative diseases. Biochim Biophys Acta. 1823, 2012: 2057-2068.

    Google Scholar 

  70. Binder LI, Frankfurter A, Rebhun LI: The distribution of tau in the mammalian central nervous system. J Cell Biol. 1985, 101: 1371-1378. 10.1083/jcb.101.4.1371.

    Article  CAS  PubMed  Google Scholar 

  71. Wang YP, Biernat J, Pickhardt M, Mandelkow E, Mandelkow EM: Stepwise proteolysis liberates tau fragments that nucleate the Alzheimer-likeaggregation of full-length tau in a neuronal cell model. Proc Natl Acad Sci U S A. 2007, 104: 10252-10257. 10.1073/pnas.0703676104.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Grabrucker AM, Garner CC, Boeckers TM, Bondioli L, Ruozi B, Forni F, Vandelli MA, Tosi G: Development of novel Zn2+ loaded nanoparticles designed forcell-type targeted drug release in CNS neurons: in vitro evidences. PLoS One. 2011, 6: e17851-10.1371/journal.pone.0017851.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by NIH/NINDS R01 NS073899.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Chad A Dickey.

Additional information

Competing interests

The authors declare that they have no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Blair, L.J., Zhang, B. & Dickey, C.A. Potential synergy between tau aggregation inhibitors and tau chaperonemodulators. Alz Res Therapy 5, 41 (2013). https://doi.org/10.1186/alzrt207

Download citation

  • Published:

  • DOI: https://doi.org/10.1186/alzrt207

Keywords