# A quantitative framework for understanding endosomal trafficking networks in Alzheimer's disease

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2020 · $459,425

## Abstract

PROJECT SUMMARY
Accumulating evidence suggest that neurodegenerative diseases including Alzheimer’s disease (AD) are
frequently the result of alterations in endosomal trafficking and proteostasis pathways, one consequence of
which can be the accumulation of aggregation-prone proteins. Numerous familial and sporadic loss or gain-of-
function mutations have been identified in such pathways, illuminating potential drivers of disease
pathogenesis. In addition, excess protein mis-folding due to altered trafficking could affect proteostasis
pathways by blocking protein turnover or trafficking. Protein and organelle trafficking within cells is a highly
dynamic and interconnected process, and defects in one arm of the system can affect other aspects of the
network in unpredictable ways including reduced flux in turnover pathways. Indeed, it is conceivable that many
seemingly unrelated mutations across the trafficking landscape in various neurodegenerative diseases reveal
common mechanistic vulnerabilities downstream but with distinct cell-type sensitivities reflective of the identity
of mis-trafficked proteins. As such, understanding the global architecture of trafficking systems and the key
machinery that controls the directionality and efficiency of trafficking, particularly of aggregation-prone
neurodegenerative proteins such as APP and its aggregation-prone form A, represents a central goal of the
field. A aggregation as a toxic driver of AD neuropathology has been a dominant hypothesis in the field.
However, thus far therapeutics directed at aggregate prevention or removal have not been successful, and
alternative hypotheses including alterations in intracellular trafficking as an important event in neuropathology
have emerged. Here, we seek to combine powerful genetic and proteomic approaches to develop a
quantitative framework for understanding how disruption of major endosomal trafficking systems – retromer
and retriever, found defective in neurodegenerative diseases – alter global membrane protein trafficking, and
specific trafficking and processing of APP proteoforms. These studies make use of an extensive tool-kit of
mutant tissue culture cell lines and induced neurons derived from human embryonic stem cell (hESC), in
combination with targeted and unbiased proteomics of individual organelles linked with endosomal trafficking,
to assemble a global map of cargo and trafficking dependencies. In parallel, we will employ novel flux-based
screening strategies to search for genes controlling APP/A trafficking to the lysosome and the plasma
membrane, and will examine the extent to which A accumulation within the endo-lysosomal system alters
selective autophagic flux using new cargo-specific reporters. The central hypothesis being tested is that
specific defects in protein trafficking networks underlies the susceptibility of neurons to A and other
aggregation prone proteins and that these defects can be molecularly unmasked through systematic netw...

## Key facts

- **NIH application ID:** 9999700
- **Project number:** 5R01NS110395-03
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** JEFFREY W HARPER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $459,425
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999700

## Citation

> US National Institutes of Health, RePORTER application 9999700, A quantitative framework for understanding endosomal trafficking networks in Alzheimer's disease (5R01NS110395-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9999700. Licensed CC0.

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