# Molecular mechanisms of selective vulnerability of neurons to tauopathy

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $744,445

## Abstract

PROJECT SUMMARY
A major challenge for the development of effective, disease-modifying therapies for Alzheimer’s disease (AD)
and related dementias (ADRD) has been our incomplete understanding of the molecular processes controlling
pathogenesis. Important clues for the key molecular pathways controlling AD/ADRD pathogenesis are likely to
be gained from the study of selective vulnerability of neurons to AD/ADRD. While different factors are likely to
contribute to selective vulnerability, our central hypothesis is that cell-autonomous pathways in neurons
contribute to selective vulnerability in AD/ADRD, and that these pathways are potential therapeutic targets to
reduce neuronal vulnerability to disease. Therefore, there is an urgent need to uncover the neuronal pathways
casually driving selective vulnerability, and to test their therapeutic potential. In order to uncover determinants of
selective vulnerability in AD, we previously used single-nucleus RNA sequencing to provide the first molecular
description of selectively vulnerable neurons in the human entorhinal cortex, a brain region affected early in AD
by tau pathology and neuronal loss. Neuronal subtypes that were lost early in disease were also selectively
affected by tau pathology. This work provided us with a list of differentially expressed genes between relatively
vulnerable versus resilient neuronal populations. The next challenge is to determine which of these differentially
expressed genes causally contributes to selective vulnerability. To establish a causal role of specific differentially
expressed genes in selective vulnerability, we will leverage CRISPRi technology, which enables the control of
expression levels of endogenous genes. CRISPRi was co-developed by MPI Dr. Kampmann, who also
pioneered CRISPRi in human iPSC-derived neurons and optimized its use in mouse brains (see preliminary
results). In a genome-wide CRISPRi modifier screen in human iPSC-derived neurons, we identified several
pathways controlling levels of tau pathology. By comparing hits from the CRISPRi screen to genes that are
differentially expressed between resilient and vulnerable neurons in the human AD brain, we uncovered
candidate resilience factors, including an CUL5 E3 ubiquitin ligase complex (Aim 1) and candidate vulnerability
factors, including key glycolytic enzymes (Aim 2). The goal of Aim 3 is to conduct a large-scale CRISPRi screen
for factors controlling tau pathology directly in the brain of tauopathy mouse models. The focus of the proposed
project is to uncover mechanisms underlying selective neuronal vulnerability in AD and ADRD. These
mechanisms represent potential therapeutic targets, and future research will test the therapeutic potential of
targeting the identified pathways. The experimental strategy we propose to establish here to uncover
mechanisms underlying selective vulnerability to tauopathy will provide a blueprint that can be applied to many
other neurodegenerative diseases.

## Key facts

- **NIH application ID:** 10667153
- **Project number:** 1R01AG082141-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** CARLO L CONDELLO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $744,445
- **Award type:** 1
- **Project period:** 2023-06-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10667153

## Citation

> US National Institutes of Health, RePORTER application 10667153, Molecular mechanisms of selective vulnerability of neurons to tauopathy (1R01AG082141-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10667153. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*