# Towards Treatment of Alzheimer’s Disease by Targeting Pathogenic Tau and Beta-Amyloid Structures

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $1,068,405

## Abstract

Project Summary
Aim 1 addresses the dearth of drugs for dementia, by structure-based drug design. This approach, so
fruitful for treating cancer and HIV-AIDS, is opening for Alzheimer’s Disease (AD) because of advances in
diffraction and cryoEM. Aggregation of protein Tau is strongly correlated with the onset of dementia. From
the recent near-atomic structure of Tau fibrils extracted from the autopsied brain of an Alzheimer’s patient,
the drug-binding site (or pharmacophore) has been determined for a fibril-disaggregatng compound. By
screening compounds that fit the pharmacophore, new Tau disaggregants have been discovered. These
disaggregants dissolve AD-brain Tau fibrils, but do not produce toxic products. From further cycles of
structure determination of complexes of Tau fibrils with the new disaggregants, followed by compound
screening, safe and effective compounds will be sought to reverse the toxic aggregation of Tau in the
brain. Synthetic chemist co-Investigator UCLA Prof. Patrick Harran will collaborate to apply a similar
approach to discover complexes of disaggregants with brain-penetrant nanoparticles.
Aim 2 proposes to fill the vacuum of knowledge of the structures of small aggregates of Tau and beta-
amyloid, known as oligomers. Numerous studies of others provide evidence that oligomers are more
cytotoxic than fibrils of the same protein. Oligomers of different fibril-forming proteins share structural
similarities in that particular antibodies (A11 & M204) recognize them, but not their corresponding fibrils.
The transient nature of oligomers has defeated previous attempts to learn their atomic structures, but our
lab has recently discovered a monoclonal Fab that extracts fairly homogeneous oligomers of Tau from AD
brains and stabilizes them long enough to make grids suitable for cryoEM structure determination.
Preliminary micrographs suggest that antibody ligands permit alignment of beta-amyloid oligomers for
cryoEM determination of structure, which may serve subsequently for design of inhibitors and
disaggregants.
Aim 3 proposes tests of AD drugs in “mini-brains” which are grown in the lab of our co-Investigator UCLA
Prof. Novitch. These organoids are the size of a BB yet display structure and electrical properties of actual
human brains. They are made from human cells and display the cell types and electrical messaging of
human brains. Preliminary work shows these mini-brains can be infected with Tau pathology, and now
the ability of our various drug candidates to interfere with the spreading and damage of aggregated Tau
can be tested in them. If successful, this approach can provide a new avenue for testing Alzheimer’s drugs
prior to human trials. For comparison, our inhibitors and disaggregants will also be assessed in a mouse
model of tauopathy.

## Key facts

- **NIH application ID:** 10370874
- **Project number:** 1R01AG070895-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** DAVID EISENBERG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,068,405
- **Award type:** 1
- **Project period:** 2022-02-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10370874

## Citation

> US National Institutes of Health, RePORTER application 10370874, Towards Treatment of Alzheimer’s Disease by Targeting Pathogenic Tau and Beta-Amyloid Structures (1R01AG070895-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10370874. Licensed CC0.

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