# Project 1: Pathobiology and Genetics of Prions Causing Alzheimer's Disease

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $605,625

## Abstract

PROJECT SUMMARY
The plaques and tangles of Alzheimer’s disease (AD) were first described over a century ago; we now know for
the first time that the proteins of these deposits are composed of Aβ and tau prions, respectively. Being able to
measure these two prions using rapid human cell bioassays in conjunction with transgenic rodent models, we
are now able to attack many areas of AD research that were previously inaccessible. We propose to expand
our cohort of 114 brain samples from patients with AD and other neurodegenerative diseases to more than
1,000 specimens from brain banks worldwide, including equal numbers of aged-matched and gender-matched
controls from cognitively normal subjects. We will survey the molecular profile of prion strains using a battery of
cell lines and proteomics and relate these findings to detailed neuropathology and whole genome sequencing
of every sample. Along these lines, we will also procure brain samples from upwards of 500 individuals with
Down syndrome (DS) because these people all develop cognitive impairment and AD neuropathology at very
young ages and have both Aβ and tau prions in their brains as we describe in this proposal. We will investigate
the influence of the APOE genotype status on the levels of Aβ and tau prions in the brains of AD and DS
patients, and perform mechanistic studies using human neural cells and humanized rodents. Importantly, we
plan to expand our studies on the induction of tau prions by Aβ prions using novel human cell and rodent
models on a background of different genetic risk factors. To identify the most relevant species of Aβ prions for
these experiments, we will create a broad repertoire of synthetic Aβ prions composed of different isoforms
informed by inherited AD mutations or genetic mosaicism as well as results from our proteomics data in human
tissue. Since studies of neural exosomes collected from patients with AD or DS show increased levels of Aβ
and tau proteins compared to controls, we plan to determine if these proteins are prions. If that proves to be
the case, then it may be possible to develop a more biologically relevant blood test for AD, which would have
enormous utility in the disease diagnosis and progression as well as the discovery of effective therapeutics.
Our collaborations described in this P01 will allow us to rapidly define the structural events that underlie the
molecular pathogenesis of AD as studied in this Project, which would seem critical to developing more effective
AD therapeutics.

## Key facts

- **NIH application ID:** 10170175
- **Project number:** 5P01AG002132-40
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** STANLEY B PRUSINER
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $605,625
- **Award type:** 5
- **Project period:** 1997-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10170175

## Citation

> US National Institutes of Health, RePORTER application 10170175, Project 1: Pathobiology and Genetics of Prions Causing Alzheimer's Disease (5P01AG002132-40). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10170175. Licensed CC0.

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