# 3D Reconstruction and Analysis of Alzheimer's Patient Biopsy Samples to Map and Quantify Hallmarks of Pathogenesis and Vulnerability

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $746,606

## Abstract

PROJECT SUMMARY/ABSTRACT
This project will expand the acquisition, reconstruction, analysis, and dissemination of 3D electron microscopic
(3D EM) reference data, disclosing key ultrastructural details preserved within a remarkable collection of legacy
biopsy brain samples from patients suffering from Alzheimer’s Disease (AD). These samples were originally
collected, characterized and archived by neuropathologists R.D. Terry and N. Gonatas (at A. Einstein in the
1960’s), with later samples taken as part of a cerebrospinal fluid (CSF) drug infusion study involving S. Mirra (at
Emory in the 1980’s). They were re-examined by Ellisman, Masliah, Terry, and Mirra in the 1980s, using early
3D EM methods, and were found to manifest excellent preservation of ultrastructure, showing paired helical
filaments (PHF) and amyloid accumulations as well as modifications to subcellular organelles and cytoskeletons
of the cell bodies, axonal and dendritic processes. Here, we will exploit recent advances in high throughput,
automated 3D EM to massively scale the examination of these precious samples, reconstructing 100s of brain
cells with and without PHF, tracking axons (and mapping glia and synapses) through much greater brain volumes
than was feasible previously. Our goal is to target areas associated with both plaques and tangles, attending to
locations where existing findings suggest cell and network vulnerability and contain molecular interactions
suspected by some to underlie the initiation and progression of AD. Supporting investigations into the
progression of soma/dendritic degeneration, we will target cells operationally defined to represent a progression
of neuronal decline as seen in AD; determining the volume fraction of PHF in the cytoplasm as a practical staging
measure and linking this to the characterization of quantitative changes in the microstructure of major subcellular
constituents. Likewise, we will analyze the progression of axonal degeneration in and near plaques as data
obtained suggests that axons may become dystrophic before their parent cell bodies and their dendrites
degenerate.

## Key facts

- **NIH application ID:** 9867232
- **Project number:** 1R01AG065549-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Mark H Ellisman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $746,606
- **Award type:** 1
- **Project period:** 2020-03-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9867232

## Citation

> US National Institutes of Health, RePORTER application 9867232, 3D Reconstruction and Analysis of Alzheimer's Patient Biopsy Samples to Map and Quantify Hallmarks of Pathogenesis and Vulnerability (1R01AG065549-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9867232. Licensed CC0.

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