Table 1.
Animal models for use in Alzheimer's disease preclinical studies
| Model | Description | Outcome | Plaques | Neurofibrillary tangles | Neuron loss | Synaptic defects | Memory defects | Notes | Reference | |
|---|---|---|---|---|---|---|---|---|---|---|
| Single-transgenic | ||||||||||
| 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. | [41-45] | |
| 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. | [46-49] |
| Multi-transgenic | ||||||||||
| 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). | [50-52] |
| 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. | [53-55] |
| 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. | [57-60] | ||
| 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. | [61-63] | |
| 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] | |
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 http://www.alzforum.org[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.