# Modulation of endosomal pathway dysfunction in Alzheimer's disease

> **NIH NIH P01** · NATHAN S. KLINE INSTITUTE FOR PSYCH RES · 2021 · $292,712

## Abstract

ABSTRACT
Neuronal early endosome pathology is among the earliest disease-specific features of Alzheimer’s disease
(AD) and has been mechanistically linked to elevated levels of -site cleaved carboxyl-terminal fragment
( CTF) of the amyloid precursor protein (APP). Pathological features of the AD early endosome phenotype
include rab5 hyperactivation, downstream disruption of the endosomal-lysosomal (EL) pathway, and a failure
of endosome-mediated trophic support. Our preliminary findings show that expression of the ApoE4 allele, the
greatest genetic-risk factor for AD, leads to alterations in neuronal early endosomes in ApoE4 mice (Core B).
Given that alterations in cholesterol metabolism in the brain have been suggested to play a role in AD and that
we find increased CTF levels in the brain with ApoE4 expression, we will test the hypothesis that ApoE4
drives CTF and cholesterol alterations that interact to promote endosomal dysfunction and downstream
lysosomal network (LN) pathology ((Project 2 (P2), P3 and P4). We will examine the lipidome and proteome of
brain endosomal fractions, isolated from ApoE4 expressing mice and humans (Core C) in order to identify the
molecular mechanism driving ApoE4 EL pathway alterations and neuronal vulnerability. We will use direct
manipulation of cholesterol in vitro and dietary challenge in vivo and manipulation of CTF levels by BACE1
downregulation to test the hypothesis that synergy between these molecules contributes to the pathological
ApoE4-driven LN phenotype. At-risk neuronal populations will be identified and examined using gene
expression analysis (P4) to elucidate the molecular mechanism of LN vulnerability. Behavioral assays will be
used to demonstrate cognitive consequences (Core C). Given the importance of endosome-to-Golgi recycling
as an exit pathway from early endosome and the recent recognition that retromer dysfunction may contribute to
AD pathobiology, we have undertaken preliminary studies to determine whether manipulation of the CTF can
rescue early endosomal pathology by stimulating the retromer pathway. We found that binding antibodies
specifically to the CTF in living cells can increase retromer-containing vesicles while reducing early
endosomal pathology. We will test the novel hypothesis that promoting CTF trafficking though the endosome-
to-Golgi recycling pathway reduces pathogenic CTF endosome-signaling and rescues pathological changes
in early endosomes and the neurodegenerative cascade this initiates. This proposal examines multiple
trafficking routes from the early endosome as well as the consequences of early endosomal dysfunction,
including impaired endosome-mediated trophic support, and, in collaboration with all of the other Projects,
downstream pathological LN changes. This represents a conceptually innovative approach to AD risk and
pathology while exploring novel molecular mechanisms – including CTF trafficking and signaling, the role of
cholesterol in CTF function, and int...

## Key facts

- **NIH application ID:** 10126776
- **Project number:** 5P01AG017617-20
- **Recipient organization:** NATHAN S. KLINE INSTITUTE FOR PSYCH RES
- **Principal Investigator:** PAUL M MATHEWS
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $292,712
- **Award type:** 5
- **Project period:** 2000-02-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10126776

## Citation

> US National Institutes of Health, RePORTER application 10126776, Modulation of endosomal pathway dysfunction in Alzheimer's disease (5P01AG017617-20). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10126776. Licensed CC0.

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