# Endosome Dysfunction in Alzheimer's Disease

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $741,201

## Abstract

Two decades ago, we identified abnormalities of rab5-positive endosomes as a signature pathology of
Alzheimer’s disease (AD), which is considered the earliest appearing neuronal pathology specific to AD yet
known. Genetic data have independently converged on endocytosis as a prime early target in AD. We have
shown that development of endosome anomalies requires pathological hyper-activation of rab5, the master
regulatory GTPase on early endosomes, to trigger markedly upregulated endocytosis and aberrant endosomal
fusion, trafficking, and cell signaling leading to cholinergic neurodegeneration. Rab5 over-activation is caused
by elevated endosomal levels of APP-ßCTF (ß-cleaved C-terminal fragment of APP) in AD and in Down
Syndrome (DS), a cause of AD due to an extra APP copy. APP-ßCTF directly binds and recruits APPL1, a
signaling effector, which aberrantly stabilizes the activated (GTP-loaded) state of rab5, triggering endosomal
dysfunction. The pathogenic importance of rab5 over-activation is underscored by the phenotype of our new
transgenic mouse model of neuronal rab5 over-activation, which develops AD-related endosome dysfunction
and AD-like deficits in retrograde transport, trophin signaling, synaptic plasticity, cognition, and neuron survival,
all reflecting impairment of rab5’s many known roles in neurons. We propose that early endosome dysfunction
is a key part of the antecedent pathobiology initiating ß-amyloidogenesis in late-onset AD and that its underlying
basis, rab5 hyper-activation, further drives AD development through multiple pathways. We further propose that
other genetic influences increasing AD risk, including ApoE and GWAS-identified genes with roles in endocytosis
increase disease risk by dysregulating rab5 or exacerbating rab5’s impact on endosome dynamics and cell
signaling. To validate these concepts, we will define the multiple pathways/factors that regulate rab5 activity in
neurons (Aim1a) and that initiate AD-related endosome dysfunction via rab5 and additional factors controlling
endosomal recycling and maturation in cell and mouse models of AD and DS (Aim 1b). We will define the
consequences of selective rab5 over-activation on brain function in vivo and validate its predicted disease-
accelerating effects in an hAPP(wt) mouse model of AD(Aim 2). Of exciting clinical relevance, we will validate in
vivo the predicted actions on endocytosis of an AD therapeutic in current clinical trials, which we have shown to
reverse rab5 activation and endosome dysfunction in DS patient cells at low nanomolar concentrations (Aim 3).
The crucial roles of APPL1 and APPL2 in directly linking APP- ßCTF to rab5 hyper-activation will be explored
and also validated in our mice that over-express APPL1 or lack APPL1 and/or APPL2 and also in these mice
crossed to AD models (Aim 4). We will test the hypothesis that GWAS AD risk genes with suspected roles in
endocytosis confer risk in part by exacerbating rab5-driven endosome dysfunction (Aim ...

## Key facts

- **NIH application ID:** 9977870
- **Project number:** 5R01AG062376-03
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** RALPH A. NIXON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $741,201
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977870

## Citation

> US National Institutes of Health, RePORTER application 9977870, Endosome Dysfunction in Alzheimer's Disease (5R01AG062376-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9977870. Licensed CC0.

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