In Vivo Models of Alzheimer’s Disease

IN VIVO ALZHEIMER'S DISEASE MODELS

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide, imposing a rapidly growing public health burden amid global population aging. Driven by complex pathophysiology—including amyloid-β (Aβ) plaque deposition, tau hyperphosphorylation, synaptic degeneration, neuroinflammation, and progressive cognitive decline—AD drug development has long faced high clinical failure rates. Validated in vivo models that faithfully recapitulate core human disease hallmarks are the cornerstone of improving preclinical predictive value and de-risking clinical translation.

Leveraging deep expertise in neuroscience disease modeling, we have established a comprehensive portfolio of in vivo AD models, encompassing both chemically induced and transgenic approaches. Our models stably reproduce key AD phenotypes from early molecular pathology to late-stage functional decline. We deliver comprehensive cognitive behavioral assessments including Open Field Test (OFT), Novel Object Recognition (NOR), Novel Object Location (NOL), Morris Water Maze (MWM), and Y-Maze test. Complementing these, our ex vivo brain slice electrophysiology platform assesses synaptic function and plasticity to capture circuit-level deficits underlying cognitive impairment. Combined with immunofluorescence (IF), Golgi staining, and transmission electron microscopy (TEM) techniques, these models support multi-layered efficacy evaluation and mechanistic dissection spanning molecular pathology, neuronal architecture, and ultrastructural readouts.

MODEL SELECTION

Translational in vivo model selection for Alzheimer's disease drug discovery

Model Type	Type	Primary Pathological Mechanism	Cognitive Deficits	Key Advantages	Key Limitations	Optimal Use Case
STZ-Induced Model	Chemically induced (non-transgenic)	Brain insulin resistance; metabolic dysfunction	Yes (3–6 weeks)	Models sporadic AD metabolic aspects; non-transgenic; relatively inexpensive	Mechanism unclear; limited Aβ pathology; no NFTs	Metabolic hypothesis studies; insulin-sensitizing drugs; diabetes-AD link
Aβ_1-42 Injection Model	Chemically induced (non-transgenic)	Exogenous Aβ neurotoxicity; neuroinflammation	Yes (1–4 weeks)	Rapid onset; no genetic manipulation; controllable Aβ dose	Acute/subacute; localized pathology; artificial Aβ source	Rapid anti-amyloid drug screening; Aβ toxicity mechanisms
Scopolamine-Induced Model	Chemically induced (non-transgenic)	Cholinergic antagonism; oxidative stress	Yes (rapid, reversible)	Very rapid onset; reversible; inexpensive for screening	No AD pathology; purely cholinergic; reversible	Cholinergic drug screening; acute cognition studies
APP/PS1 Transgenic Model	Transgenic	APP overexpression; increased Aβ_1-42 production	Yes (6–12 months)	Well-characterized; robust amyloid pathology; widely available	No NFTs; APP overexpression artifacts; no neuronal loss	Anti-amyloid therapy development; plaque biology; microglial responses
5×FAD Transgenic Model	Transgenic	Massive APP overexpression; aggressive Aβ_1-42 production	Yes (4–5 months)	Very rapid pathology; early cognitive deficits; neuronal loss	Overly aggressive; APP overexpression artifacts; no NFTs	Rapid drug screening; early-stage interventions; neuronal loss studies
3×Tg-AD Transgenic Model	Transgenic	APP + tau overexpression; Aβ-driven tau pathology	Yes (4–6 months)	Both Aβ and tau pathologies; progressive disease sequence	TauP301L is FTD mutation; multiple transgenes; sex differences	Combination therapy testing; Aβ-tau interaction studies; disease progression

VALIDATED MODEL LIBRARY

Explore the model-specific validation workflow

Select a model below to review its biological rationale, experimental design, efficacy readouts, and representative data.

01STZ-Induced Rat Model

This model is induced by intracerebroventricular (ICV) administration of streptozotocin (STZ). ICV delivery of STZ impairs cerebral insulin signaling, triggering downstream mitochondrial dysfunction, oxidative stress, neuroinflammation, and progressive neuronal loss. These pathological changes collectively drive synaptic dysfunction, tau hyperphosphorylation, and AD-like cognitive impairment. Following model establishment, Donepezil is administered once daily by oral gavage for 28 consecutive days, followed by comprehensive behavioral testing (OFT, NOR, MWM) and brain histopathological analysis.

Experimental Flow Design

Experimental flow design of STZ-induced rat model

Behavioral Characterization

The STZ-induced Alzheimer's disease rat model successfully recapitulated key behavioral deficits, including hyperactivity, anxiety-like behavior, impaired recognition memory, and spatial learning deficits. These abnormalities were effectively ameliorated by donepezil.

Behavioral characterization of STZ-induced rat model

Pathological & Mechanistic Validation

6E10 (Aβ deposition): STZ treatment markedly increased 6E10 immunoreactivity, which was significantly reduced by donepezil, indicating attenuation of amyloid pathology.

6E10 Aβ deposition staining in STZ model

Iba1 (Microglial activation): STZ treatment significantly increased Iba1-positive microglia, while donepezil effectively suppressed microglial activation.

Iba1 microglial activation staining in STZ model

GFAP (Astrocyte activation): GFAP expression was markedly elevated in the STZ model and was significantly reduced following donepezil treatment, indicating attenuation of astrocyte activation.

GFAP astrocyte activation staining in STZ model

02Aβ_1-42-Induced Mouse Model

The Aβ_1-42-induced model is an acute Alzheimer's disease model established by bilateral intracerebroventricular administration of Aβ_1-42, leading to rapid induction of Aβ-associated neuronal dysfunction and cognitive deficits. After a 2-week post-injection period, behavioral tests (OFT, NOL, MWM) are conducted, followed by brain collection for pathological analysis.

Experimental Flow Design

Experimental flow design of Aβ1-42-induced mouse model

Behavioral Characterization

Aβ_1-42 ICV injection produced a broad behavioral phenotype characterized by reduced spontaneous locomotor activity, increased anxiety-like behavior, impaired spatial recognition, and deficits in spatial learning and memory, confirming successful behavioral establishment of the model.

Behavioral characterization of Aβ1-42-induced mouse model

Pathological & Mechanistic Validation

Systemic Inflammatory Response: Serum IL-1β, IL-6, and TNF-α levels were markedly elevated, evaluating the systemic inflammatory response associated with Aβ_1-42-induced pathology.

Systemic inflammatory response in Aβ1-42 model

Amyloid Pathology: Aβ_1-42 ICV injection markedly increased brain Aβ_1-42 immunofluorescence compared with WT controls, confirming enhanced amyloid pathology in the model.

Amyloid pathology in Aβ1-42 model

03Scopolamine-Induced Rat Model

The scopolamine model is primarily a cholinergic cognitive-impairment model, rather than a full pathological AD model, as it does not replicate Aβ plaques, neurofibrillary tangles, or progressive neurodegeneration. It is established by daily co-administration of scopolamine (i.p.) and donepezil (oral gavage) for 2 weeks. Behavioral tests (NOR, Y-Maze, MWM) are conducted following the 2-week drug administration period.

Experimental Flow Design

Experimental flow design of scopolamine-induced rat model

Behavioral Characterization

The scopolamine-induced cognitive impairment model successfully recapitulated key behavioral deficits, including impaired recognition memory, spatial learning dysfunction, and diminished short-term spatial working memory. These abnormalities were effectively ameliorated by donepezil, validating a robust and pharmacologically responsive system for preclinical screening of cognition-enhancing therapeutics.

Behavioral characterization of scopolamine-induced rat model

04APP/PS1 Double-Transgenic Mouse Model

The APP/PS1 transgenic mouse is a widely used genetic model of familial Alzheimer's disease that co-expresses mutant human amyloid precursor protein (APP) and presenilin-1 (PS1), resulting in progressive Aβ accumulation and amyloid plaque formation. The APP/PS1 double-transgenic mice receive donepezil once daily by oral gavage for 3 consecutive months, followed by comprehensive behavioral testing (NOR, Y-Maze, MWM) and brain histopathological analysis.

Experimental Flow Design

Experimental flow design of APP/PS1 double-transgenic mouse model

Behavioral Characterization

APP/PS1 mice exhibited a broad behavioral phenotype characterized by increased locomotor activity and deficits in recognition, spatial working, and spatial memory. Chronic donepezil treatment consistently ameliorated these behavioral abnormalities, demonstrating the pharmacological responsiveness of the APP/PS1 model.

Behavioral characterization of APP/PS1 mouse model

Pathological & Mechanistic Validation

6E10 (Amyloid pathology): APP/PS1 mice showed prominent amyloid plaque deposition, which was attenuated by chronic donepezil treatment.

6E10 amyloid pathology in APP/PS1 model

P-Tau (Tau pathology): APP/PS1 mice exhibited significant tau hyperphosphorylation, which was reduced following donepezil treatment.

P-Tau tau pathology in APP/PS1 model

Iba1 (Microglial activation): APP/PS1 mice displayed marked microglial activation, which was effectively suppressed by donepezil.

Iba1 microglial activation in APP/PS1 model

Golgi Staining: APP/PS1 mice showed reduced density and maturation of dendritic spines in the CA1 and DG regions, which was restored by donepezil.

Golgi staining of dendritic spines in APP/PS1 model

TEM: APP/PS1 mice exhibited mitochondrial ultrastructural damage, which was ameliorated by donepezil.

TEM mitochondrial ultrastructure in APP/PS1 model

Hippocampal Neurotransmitter Levels: APP/PS1 mice showed depletion of ACh, DA, and 5-HT, which was reversed by donepezil.

Hippocampal neurotransmitter levels in APP/PS1 model

055×FAD Transgenic Mouse Model

The 5×FAD transgenic mouse model is an aggressive amyloid-focused familial AD model carrying five familial AD mutations—three in APP and two in PSEN1—that drive rapid Aβ accumulation, amyloid deposition, gliosis, neurodegeneration, and cognitive deficits. 5×FAD transgenic mice receive donepezil once daily by oral gavage for 2 consecutive months, followed by comprehensive behavioral testing (NOR, MWM) and brain histopathological analysis.

Experimental Flow Design

Experimental flow design of 5xFAD transgenic mouse model

Behavioral Characterization

The 5×FAD model reproduced key AD phenotypes, including impaired recognition and spatial memory, while chronic donepezil treatment significantly ameliorated these behavioral deficits.

Behavioral characterization of 5xFAD transgenic mouse model

Pathological & Mechanistic Validation

6E10 (Amyloid pathology): 5×FAD mice exhibited prominent amyloid plaque deposition, which was significantly attenuated by chronic donepezil treatment, demonstrating the model's utility for rapid anti-amyloid drug evaluation and early-stage intervention studies.

6E10 amyloid pathology in 5xFAD model

063×Tg-AD Triple-Transgenic Mouse Model

The 3×Tg-AD mouse is a triple-transgenic Alzheimer's disease model carrying human mutant APP, PSEN1, and MAPT (tau) genes. It is one of the widely used models that recapitulates both amyloid-β and tau-related AD pathology, together with progressive synaptic dysfunction and cognitive impairment.

Experimental Flow Design

Experimental flow design of 3xTg-AD triple-transgenic mouse model

Behavioral Characterization

The 3×Tg-AD mice showed persistent spatial learning and memory deficits from 3–9 months in Morris Water Maze (MWM) test, demonstrating a robust longitudinal cognitive phenotype.

Behavioral characterization of 3xTg-AD mouse model

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