# Elucidating the role of Adaptor Protein complex-4 in regulating axonal autophagic and lysosomal pathways

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2022 · $533,231

## Abstract

The autophagic and lysosomal pathways (ALP) clear misfolded proteins and damaged organelles from cells.
Their function is therefore particularly critical for long-lived cells such as neurons. Dysfunction in the ALP is
associated with various stages of Alzheimer’s disease (AD). This includes the robust accumulation of
autophagosomes and lysosome-like organelles in dystrophic axons around extracellular Aβ deposits (Amyloid
plaques), which are hallmark pathological features observed in human Alzheimer’s disease brain tissue and
recapitulated in transgenic mouse models of Alzheimer’s disease. Amyloid plaque formation has been directly
linked to aberrant/amyloidogenic proteolytic processing of amyloid precursor protein (APP) by secretases.
However, whether abnormal trafficking and accumulation of these organelles bearing these protein cargoes
trigger this critical pathogenic event in Alzheimer’s disease, has not been experimentally addressed. In addition,
information on mechanisms and specific molecular components regulating ALP in axons remains limited.
Elucidating these mechanisms and identifying molecular components might enable therapeutic modulation of
neuronal ALP to reduce amyloid plaque burden and toxic Aβ peptide production in Alzheimer’s disease. To this
end, our proposed research seeks to understand a) how the adaptor complex, AP-4, regulates axonal
autophagosome and lysosome biogenesis, maturation, and transport; b) how loss of AP-4 contributes to amyloid
plaque formation in vivo as well as potentially identify new AP-4 cargo that facilitate optimal retrograde axonal
lysosome transport, APOE metabolism, and synaptic activity. Central to these proposed studies is our
preliminary data that AP-4 loss causes abnormal accumulation of ALP organelles in axonal swellings reminiscent
of AD pathology, including build-up of APP cleaving proteins BACE1 and PSEN2. This and our preliminary data
demonstrating reduced AP-4 levels in AD mouse brain and an age-dependent loss of AP-4 in the pre-frontal
cortex of even wild type mice lead us to hypothesize that AP-4-dependent axonal autophagosome and lysosome
maturation and transport protects neurons from amyloidogenic APP processing and thus, from amyloid plaque
development. Additionally, our use of super-resolution microscopy on ALP organelles in axonal swellings as well
as proteomics on isolated axons and organelles upon loss of AP-4 complex, will yield novel insight into the kinds
of ALP intermediates accumulating under these pathological conditions and their relative contributions to build-
up of APP processing machinery. Our proposed efforts to dissect out AP-4 mediated axonal ALP transport and
maturation could also lead to new therapeutic opportunities that focus on mobilizing these axonal ALP organelles
to limit Aβ production and axonal pathology. Furthermore, new insights into cell biology of neuronal autophagic
and lysosomal pathways revealed by our studies could have broader relevance to other neuro...

## Key facts

- **NIH application ID:** 10531491
- **Project number:** 1R01AG074248-01A1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Swetha Gowrishankar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $533,231
- **Award type:** 1
- **Project period:** 2022-09-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10531491

## Citation

> US National Institutes of Health, RePORTER application 10531491, Elucidating the role of Adaptor Protein complex-4 in regulating axonal autophagic and lysosomal pathways (1R01AG074248-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10531491. Licensed CC0.

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