# a-Synuclein vulnerability mechanisms and therapeutics in Alzheimer's Disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $395,000

## Abstract

Project Summary/Abstract
Alzheimer’s disease (AD) is characterized by the accumulation of multiple proteins including (APP)/Aβ, Tau,
TDP-43 and alpha-synuclein (α-syn). The mechanisms are not completely understood however alterations in
protein aggregate clearance including endosomal sorting complex required for transport (ESCRT) mediated
autophagy might be involved. For the previous period of funding, the focus was to investigate the role of
autophagy in the mechanisms of propagation and clearance of α -syn and to develop new immunotherapies for
the Dementia with Lewy bodies (DLB). We found that α -syn interferes with intracellular trafficking and
autophagy and that treatment with antibodies reduced propagation and toxicity. We published over 150
manuscripts and 3 of our programs targeting α -syn have advanced to Phase I clinical trials. In the renewal, we
investigated the role of α -syn as a mediator of the toxicity of Aβ to selected neuronal populations in AD. Our
HYPOTHESIS is that via interactions with Rabs and ESCRTIII proteins, α -syn aggregates interfere with
neuronal endosomal transport of neurotrophic factors (NTFs) leading to selective neuronal damage.
Our OBJECTIVES: i) investigate the role of α -syn as mediator of the selective neuronal loss in AD by
interfering with Rabs and ESCRTIII leading to defective transport of NTFs and ii) assess if brain-penetrating
nucleotides targeting α -syn might reverse the endosomal alterations and protect selected networks from
degenerating in AD. Our revised AIMS: 1) Investigate in neuronal cultures the mechanisms through which α -
syn mediates selective neuronal vulnerability in AD via alterations in Rabs and ESCRTIII; 2) To determine in
vivo if conditional ablation of α -syn in specific neuronal populations in APP mice ameliorates
neurodegeneration and functional alterations and 3) To evaluate the neuroprotective effects of brain targeted
α -syn siRNA in APP tg models. These goals are in agreement with the NIA 2012 and 2015 AD Summit
Research Recommendations. A better understanding of the mechanisms underlying selective vulnerability in
AD is crucial for developing novel therapeutics targeting α -syn.

## Key facts

- **NIH application ID:** 10360204
- **Project number:** 3R01AG018440-20S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Robert Rissman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $395,000
- **Award type:** 3
- **Project period:** 2001-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10360204

## Citation

> US National Institutes of Health, RePORTER application 10360204, a-Synuclein vulnerability mechanisms and therapeutics in Alzheimer's Disease (3R01AG018440-20S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10360204. Licensed CC0.

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