Modeling Alzheimer Disease Pathology
The Amyloid Cascade
Amyloid pathology remains central to Alzheimer disease modeling. Accumulation of amyloid beta (Aβ) peptides, derived from amyloid precursor protein (APP), drives plaque formation and downstream neurotoxicity.
Tau Pathology
Tau hyperphosphorylation and neurofibrillary tangle formation correlate closely with cognitive decline in AD. Tau models enable study of this critical pathological feature.
Combined Amyloid and Tau Models
The interaction between amyloid and tau pathology is a key focus of AD research. Models combining both pathways enable study of:
Model Types for Alzheimer Research
APP Knockin Models
APP knockin models express familial AD mutations from the endogenous App locus, providing physiological expression levels and normal regulatory control. APP knockin models develop amyloid pathology progressively, better modeling the age dependent nature of AD compared to high expressing transgenic approaches.
Transgenic Overexpression Models
Transgenic models expressing mutant APP, PSEN1, or tau under strong promoters develop pathology rapidly. Overexpression models provide faster pathology development but may include artifacts from supraphysiological protein levels.
Conditional Approaches
Conditional models enable temporal and spatial control over AD gene expression:
Inducible APP/tau expression
Trigger pathology onset in adult animals
Cell type specific expression
Restrict pathogenic proteins to neurons or glia
Adult onset models
Bypass developmental effects to model late onset disease
Tau Models
| Model Type | Features | Applications |
|---|---|---|
| PS19 | P301S tau, aggressive tangle pathology | Tau spreading, neurodegeneration |
| rTg4510 | Regulatable P301L tau expression | Temporal control, tau clearance studies |
| Tau knockin | Human MAPT from endogenous locus | Physiological tau biology |
| MAPT humanized | Complete human tau gene replacement | Human specific tau biology |
Knockin vs Transgenic Approaches
Knockin models provide more physiologically relevant disease modeling but require longer timelines for pathology development. Transgenic models offer faster readouts but may include artifacts from overexpression.
Research Applications
Understanding Disease Mechanisms
Genetically engineered mouse models have been essential for understanding AD pathophysiology:
- Amyloid processing and aggregation
- Tau phosphorylation and spreading
- Microglial activation and neuroinflammation
- Synaptic dysfunction and neurodegeneration
- Blood brain barrier disruption
- Gut microbiota brain axis interactions
Therapeutic Testing
AD mouse models provide platforms for preclinical efficacy testing:
- Anti amyloid therapeutics (antibodies, secretase inhibitors)
- Tau targeting approaches (aggregation inhibitors, immunotherapy)
- Neuroprotective strategies
- Combination therapies
Phenotypic Assessments
Pathological Endpoints
- Amyloid plaque quantification (immunohistochemistry, Congo red, Thioflavin S)
- Tau phosphorylation and tangle formation
- Microglial and astrocyte activation
- Synaptic protein levels
- Neuronal loss
Behavioral Endpoints
- Spatial learning and memory (Morris water maze, Barnes maze)
- Recognition memory (novel object recognition)
- Working memory (Y maze, T maze)
- Fear conditioning
- Nest building and activities of daily living
Selected Publications in Alzheimer Disease
Models generated by ingenious targeting laboratory have supported Alzheimer disease research:
Vacher CM et al. (2021).
Placental endocrine function shapes cerebellar development and social behavior. ↗Nature Neuroscience 24(10): 1392-1401
Chakrabarti S et al. (2024).
Touch sensation requires the mechanically gated ion channel ELKIN1. ↗Science 383(6686): 992-998
Clausen BE et al. (1999).
Conditional gene targeting in macrophages and granulocytes using LysMcre mice. ↗Transgenic Research 8(4): 265-277
What Researchers Say
“ingenious Targeting Laboratory is highly recommended for generating custom animal models. Past 2 years, we have made 2 conditional knockout mouse lines. All processes of each project were scientifically and professionally handled. Their scientific consulting to initiate the project was superb compared to other companies, and transparency of the project progress reported by project managers was excellent. Their excellency and dedication to meet our needs in a timely manner are invaluable to continuation of our research progress.”
— Hyekyung Plumley, PhD
Warren Center for Neuroscience Drug Discovery
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