# Mechanisms of brain phenotypes caused by FAD-linked Presenilin-1 Mutations

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $588,406

## Abstract

Project Summary/Abstract
Mutations in the PSEN1 and PSEN2 genes encoding Presenilin-1 (PS1) and Presenilin-2 (PS2) are the most
common cause of familial Alzheimer's disease (FAD), highlighting the importance of Presenilin function in
disease pathogenesis, but the underlying mechanisms remain unresolved. Aberrant APP processing by γ-
secretase and γ-secretase-independent activities of PS1 have been implicated in FAD pathogenesis. Our
recent work has shown surprisingly that pathogenic mutations in PS1 can inactivate its function as the catalytic
subunit of the γ-secretase complex and produce FAD-related phenotypes through a loss-of-function
mechanism. To assess the effects of FAD mutations in vivo, particularly in the brain where the pathogenic
process occurs, we generated two independent lines of Psen1 knock-in (KI) mice that precisely reproduce
chromosomal PSEN1 mutations identified in FAD patients. Our analysis revealed phenotypes in the resulting
homozygous KI mice indistinguishable from those caused by a Psen1 null mutation, accompanied by
essentially complete loss of γ-secretase activity in the brain. Heterozygosity for the Psen1 L435F KI mutation
produced deficits in hippocampal short- and long-term synaptic plasticity and hippocampal learning and
memory reminiscent of those caused by conditional inactivation of Presenilins in the adult brain. Intriguingly,
heterozygous KI mice also displayed elevation of the cortical Aβ42/Aβ40 ratio and exacerbation of cortical Aβ
deposition on a mutant APP transgenic background. Moreover, the Psen1 L435F KI mutation was unable to
support neuronal survival in the aging brain, triggering widespread cerebral cortical neurodegeneration. In this
competing renewal application, we propose to investigate the important questions of whether and to what
extent these synaptic, behavioral, and neurodegenerative phenotypes caused by the FAD mutation are
attributable to aberrant APP processing and impaired γ-secretase activity, or alternatively to APP-independent
and/or γ-secretase-independent functions of PS1. We propose to perform multidisciplinary molecular, synaptic,
behavioral, and histological analysis using novel mouse models to understand the contributions of APP
processing and γ-secretase-independent activity to Presenilin function and FAD-related dysfunction in the adult
brain. The results of our studies will have significant impact on understanding of FAD pathogenesis and
strategies to devise effective therapies.

## Key facts

- **NIH application ID:** 9957204
- **Project number:** 5R01NS075346-10
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Raymond J Kelleher
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $588,406
- **Award type:** 5
- **Project period:** 2011-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9957204

## Citation

> US National Institutes of Health, RePORTER application 9957204, Mechanisms of brain phenotypes caused by FAD-linked Presenilin-1 Mutations (5R01NS075346-10). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9957204. Licensed CC0.

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