# Studies of dementia pathogenesis in genetically faithful rat models of Familal Alzheimer disease

> **NIH NIH R01** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2021 · $786,979

## Abstract

Project Summary/Abstract
 Alzheimer's Disease (AD) is the most common cause of ageing-dependent dementia in the world and is
associated with cerebral amyloid plaques, mostly composed of Aβ peptides. These peptides are produced by
a double cleavage of the amyloid precursor protein (APP). BACE1 cleavage produces the C-terminal
fragment, β-CTF, which is then processed into several Aβ isoforms by γ-secretase. Genetic data suggest that
regulation of APP processing contributes to AD. In addition, a polymorphism of APP that reduces processing
of APP by BACE1 protects from sporadic AD and from normal aging-dependent cognitive decline. Thus, the
human genetic evidence indicates that APP and APP processing are important for normal cognitive functions.
To gain insights into the pathogenic mechanisms of AD we introduced a familial APP mutation (the Swedish
K670N/M671L mutation, AppS rats) and a familial PSEN1 mutation (L435F, Psen1LF rats) into the genomic App
and Psen1 rat loci, respectively. Rat and human APP differ by 3 amino-acids in the Aβ region: given that
aggregated forms of Aβ are considered by most the main pathogenic factor in AD, and given that human Aβ
may have higher propensity than rodent Aβ to form yet-to-be-identified toxic forms of Aβ, together with the
Swedish mutations we introduced mutations to “humanize” the rat Aβ sequence. As controls, we produced
rats carrying only the humanized Aβ sequence (Apph rats). We choose a knock in (KI) approach rather than
the more common transgenic overexpression approach because KI models make no preconceived
assumption about pathogenic mechanisms, except the unbiased genetic one. In contrast, transgenic models,
which produce high levels of A and can readily deposit amyloid plaques, are based on the hypothesis that
plaques and/or other forms of toxic A have a central pathogenic role. We propose to dissect pathogenic
mechanisms of neurodegeneration using these KI rat models of FAD. We will study the impact of App and
Psen1 FAD mutations on APP processing, brain pathology, neuro-inflammation and neurodegeneration,
synaptic transmission/plasticity, learning & memory. In addition, we will assess the role of distinct APP-derived
metabolites in neurodegenerative processes triggered by mutant APP and PSEN1. These studies will test the
mainstream hypotheses but also consider alterative pathogenic mechanisms, including the possibility that
FAD pathogenesis may depend on the alteration of the normal function of APP and PSEN1 in the brain.

## Key facts

- **NIH application ID:** 10128348
- **Project number:** 5R01AG063407-03
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** LUCIANO D'ADAMIO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $786,979
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10128348

## Citation

> US National Institutes of Health, RePORTER application 10128348, Studies of dementia pathogenesis in genetically faithful rat models of Familal Alzheimer disease (5R01AG063407-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10128348. Licensed CC0.

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