# The role of cell death pathways in mediating neuronal loss during the earliest stages of Alzheimer disease

> **NIH NIH K01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $130,211

## Abstract

ABSTRACT
The purpose of this K01 proposal is to provide me with the necessary mentored training to become an
independent investigator studying the role of cell death pathways that mediate neuronal loss in individuals with
Alzheimer's disease (AD). Neuronal death is a key feature of AD and the best correlate of cognitive impairment
and dementia, with neurofibrillary tangle (NFT) pathology being the next-best risk factor. It is currently unknown
which mechanisms promote neuronal death in early AD or how these are linked to NFTs. Studies in
postmortem AD brains have demonstrated the activation of caspase-mediated cell death pathways, as well as
disruption of ubiquitin-proteasome (UPS)-mediated proteolysis. The overall objective of this proposal is to
study the interplay between caspases, defective UPS-mediated tau proteostasis and NFT pathology in
mediating AD neuronal loss in two nuclei of the human brainstem showing the earliest vulnerability to NFTs:
the dorsal raphe nucleus (DRN) and locus ceruleus (LC). We will make use of a unique collection of well-
characterized human brains across the AD stages, specifically enriched with early AD brain samples, and a
human-derived neuronal culture model for follow-up studies on the mechanisms of caspase activation, tau
toxicity and cell death. My central hypothesis is that neuronal dysfunction and subsequent death in AD is
mediated by an imbalance between caspase-cleaved tau and defective UPS tau clearance. I will test this
hypothesis by pursuing the following specific aims: (1) Determine the relationship between caspase
activation, caspase-cleaved tau and neuronal death in progressive stages of AD (2) Examine the role of
caspases, the UPS and the co-chaperone CHIP (C terminus of the Hsc70-interacting protein) in
mediating neuronal death and NFT pathology in progressive stages of AD. (3) Determine the role of
caspase activation, the ubiquitin-proteasome system and CHIP in mediating neuronal death and tau
pathology to patient-derived neuronal cell culture. This proposal is significant because it will generate a
precise map of the interaction between cell death mechanisms and the proteasome system in mediating early
neuronal death and NFTs in AD. This proposal is innovative because interventions targeting early cell death
pathways in AD will promote the development of novel biomarkers and therapeutic targets. UCSF and the
Gladstone Institute are ideal environments for my proposed training as they provide outstanding research
facilities, training resources and excellent mentorship readily available within our scientific community.
Completion of the proposed research and career development activities will inform the development of an R01
proposal for conducting independent research on the molecular profiles of the active cell death markers in AD
using proteomic analyses. Our findings could inform experimental strategies on revised models for preventing
AD pathogenesis before the cognitive changes appear, thus ...

## Key facts

- **NIH application ID:** 10176314
- **Project number:** 5K01AG053433-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Panagiotis Theofilas
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $130,211
- **Award type:** 5
- **Project period:** 2017-07-01 → 2021-12-03

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10176314

## Citation

> US National Institutes of Health, RePORTER application 10176314, The role of cell death pathways in mediating neuronal loss during the earliest stages of Alzheimer disease (5K01AG053433-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10176314. Licensed CC0.

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