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Table 1 Animal models for use in Alzheimer's disease preclinical studies

From: Accelerating drug discovery for Alzheimer's disease: best practices for preclinical animal studies

  Model Description Outcome Plaques Neurofibrillary tangles Neuron loss Synaptic defects Memory defects Notes Reference
APP familial mutation models Tg2576 (APP Swedish) Mutations at beta-secretase cleavage site (aa 670/1) Enhanced cleavage by beta-secretase; overall more Aβ (all forms) Yes:
9-12 months
No No Yes Yes Pathology includes mostly dense cored plaques and some tau hyperphosphorylation with age. Synaptic and memory defects generally precede amyloid deposits. Moderate oxidative stress can be detected. [36]
  PDAPP, APP London V717W (APP Indiana) Mutations at gamma-secretase cleavage site (aa 717) Enhanced cleavage by gamma-secretase; increased Aβ 42:40 ratio Yes:
9-12 months
No No Yes Yes These models demonstrate higher levels of diffuse amyloid deposits. [37, 38]
  TgAPParc, APPDutch Mutations within Aβ sequence (aa 692/3/4) Enhanced Aβ aggregation Yes:
9-12 months
No No Yes Yes These models demonstrate pronounced cerebral amyloid angiopathy. [39, 40]
  APPArcSwe/Tg-SwDI/hAPPsw/Ind/Arctic Multiple APP familial mutations Enhanced amyloid pathology over single mutation Yes: variable No No Yes Yes Example models include TgCRND8 and J20 mouse models. [4145]
Tau JNPL3, MAPT (P301L), MAPT(VLW), Tau406W Point mutations in human MAPT (FTD mutations; no tau mutations linked to AD) Increased tau phosphorylation/aggregation No Yes (>6 months) Yes Yes Yes Significant lower motor neuron loss, limb paralysis, and prominent brainstem and spinal cord pathology in some strains may impede behavioral testing. Inducible promoter models (Tg4510) and hTau models show more forebrain pathology and are better for cognitive behavior analysis. [4649]
APP/PS APP(swe)/PS1(M146L), APP(swe)/PS1(A246E) Double-transgenic (APP FAD mutant overexpression, PS FAD mutant expression, or knock-in) Accelerated phenotype and pathology but minimal neurodegeneration Yes:
3-6 months
No No Yes Yes Significant hippocampal neuron loss is seen in some subtypes (for example, APP(swe+lon)/PS1). [5052]
APP/Tau APP(swe)/tau (P301L), APP (swe)/tau (VLW) Double-transgenic (APP FAD mutant overexpression and tau FTD mutant overexpression) Accelerated phenotype and pathology but minimal neurodegeneration Yes: 9 months Yes Yes Yes Yes These models demonstate increased amyloid deposition compared with Tg2576, but there are reports of high death rate and difficulty breeding. [5355]
APP/PS/Tau 3xTgAPP [APP(swe)/PS1(M146V)/MAPT (P301L)] Triple-transgenic; FAD APP and FTD tau transgenes in PS1 FAD knock-in Accelerated phenotype and pathology, including NFTs Yes:
3-6 months
Yes Yes Yes Yes This model demonstrates early intraneuronal deposits and plaques preceding tangles. [56]
APP/NOS2-/- APP(swe)/NOS2-/-, APP(SweDI)/NOS2-/- APP transgenic (Swedish alone or combined with other APP mutations) on a NOS2 knockout background Increased tau pathology (hyperphosphorylation, redistribution, aggregation) and neuronal degeneration Yes:
3-6 months
Some Yes Yes Yes Increased caspase-3 activation is seen along with higher levels of insoluble Aβ compared with single APP transgenic mice (only in APP(swe) not APP(SweDI) line), cerebral amyloid angiopathy, and neurovascular changes. [32, 34]
Non-transgenic models
  Aged rodent models (mice, rats, dogs, and non-human primates) Old age >18-20 months   Yes: dogs and non-human primates No No Yes Yes These models show cognitive deficits, brain hypometabolism, cholinergic defects, altered calcium homeostasis, oxidative stress, and neophobia. [5760]
  SAMP8 Spontaneously mutated inbred strain: senescence-accelerated prone mice Shortened lifespan and accelerated aging phenotype. Elevated levels of endogenous (murine) APP and Aβ No No No Yes Yes (>2 months) Some tau hyperphosphorylation is seen along with decreased spine density and synaptic proteins. Increased gliosis and systematic oxidative stress are seen. [6163]
  Acute Aβ injection Direct injection of Aβ into the brain via cannulas Acute local Aβ elevation No No No Yes Yes The Aβ type/preparation method is crucial. Types synthetic and natural (from culture or brain). Preparation methods water, ammonium bicarbonate, HFIP, and DMSO. Aβ conformations monomers, oligomers (ADDLs), or fibrils. Standardized protocols for this model are needed. [64, 65]
  Induced ischemia Occlusion of cerebral artery Oxygen deprivation No No Yes Yes Yes Many models/techniques are available to induce ischemia. Infarct size can be variable. [66]
  Toxin-induced lesions Direct injection of toxin (for example, STZ, IgG-192 saporin, 6-OH, and MPTP) Neuronal degeneration/dysfunction in specific brain regions No No Yes Yes Depends on neuronal populations that are affected STZ model - In addition to cognitive decline, impairment of cholinergic transmission, oxidative stress, and astrogliosis are seen. IgG-192 saporin model - cholinergic dysfunction is seen. MPTP and model - dopaminergic cell loss and motor phenotypes are seen. [67, 68]
  1. This partial list of available strains serves to highlight the classes of models used in preclinical studies. For an extensive list of available models, please visit[69]. Aβ, amyloid-beta; ADDL, amyloid-beta-derived diffusible ligand; APP, amyloid precursor protein; DMSO, dimethyl sulphoxide; FAD, familial Alzheimer's disease; FTD, frontotemporal dementia; HFIP, 1,1,1,3,3,3-hexafluor-2-propanol; MAPT, microtubule-associated protein tau; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NFT, neurofibrillary tangle; NOS2, nitric oxide synthase 2; PS, presenilin; siRNA, small interfering RNA; STZ, streptozotocin.