# Localization of fibrillar polymorphs in human brain tissue

> **NIH NIH R21** · NORTHEASTERN UNIVERSITY · 2020 · $431,750

## Abstract

Localization of fibrillar polymorphs in human brain tissue
Summary
Fibrillar aggregates of A peptides and tau protein are defining features of Alzheimer's disease
(AD) but the role these structures play in the etiology of disease remains uncertain. High
resolution cryo-electron microscopy (cryo-EM) and solid-state NMR (ssNMR) have been used to
generate a host of molecular models of fibrillar polymorphs, some or all of which may be relevant
to disease. These structural models have provided the foundation for studies demonstrating an
association of specific polymorphs with different disease subtypes. Outstanding questions remain
as to the distribution of polymorphs between and within cases. The proposed work will apply, in
situ, a structural technique that has resolution higher than immunostaining; is very sensitive to
amyloid structure; can distinguish between fibrillar polymorphs; and keeps anatomical and spatial
relationships intact. Preliminary data show that it can probe both tangles and plaques in intact
unstained tissue. In agreement with other techniques, these data indicate that there are
polymorphs of A structure between and within cases. Analogous associations have yet to be
demonstrated for tau deposits, and those associations will be tested here. The central
hypothesis of the proposed work is that the spatial distribution of structural polymorphs
in brain tissue will provide important clues as to how fibrils contribute to disease. In the
proposed studies, X-ray microdiffraction (XMD) of histological sections of brain tissue will be used
to map the locations of fibrillar polymorphs of both A and tau, generating sub-cellular (~ 5 
resolution maps of polymorph abundances across millimeter-scale regions of interest. Initial work
(Specific Aim 1) will map the distribution of A and tau polymorphs in human brain tissue in
sporadic AD cases, including samples from several brain regions. These results will be compared
(Specific Aim 2) to analogous results from (i) MAPT mutant cases, (ii) PS1 cases and to (iii) cases
of occipital predominant visuo-spatial AD. Comparison to MAPT mutants will demonstrate
whether tau fibrils with distinct molecular morphologies exhibit preservation of conformational
signatures during disease spread; comparison with PS1 cases will provide analogous information
for A fibrils; comparison with occipital predominant visuo-spatial AD will probe fibrillar
conformations and polymorph distributions in disease with distinctly different patterns of
progression. The results of these studies will provide a preliminary assessment of whether or not
different fibrillar polymorphs spread by a prion-like process during disease progression and
provide insights into the mechanisms by which different strains are associated with different
disease subtypes.

## Key facts

- **NIH application ID:** 10043200
- **Project number:** 1R21AG068972-01
- **Recipient organization:** NORTHEASTERN UNIVERSITY
- **Principal Investigator:** LEE MAKOWSKI
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $431,750
- **Award type:** 1
- **Project period:** 2020-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10043200

## Citation

> US National Institutes of Health, RePORTER application 10043200, Localization of fibrillar polymorphs in human brain tissue (1R21AG068972-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10043200. Licensed CC0.

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