# Insights into Amyloid Pathogenicity Dynamics

> **NIH NIH R21** · NORTHWESTERN UNIVERSITY · 2024 · $170,112

## Abstract

ABSTRACT
 Alzheimer’s disease (AD) is an incurable brain disorder that currently debilitates more than 40 million
people worldwide. Clinically, AD typically presents as a slow and progressive decline in cognitive performance
that inevitably culminates in severe dementia. AD is confirmed postmortem by dementia with amyloid beta (Aβ)
peptides plaques and neurofibrillary tangles (NFTs) containing the hyper-phosphorylated Tau protein. A
situation which proves that the normal pathways required for protein degradation are impaired in AD brain. It is
generally accepted that plaques and tangles play complex roles in AD and that changes in Aβ metabolism
precipitate a damaging cascade upstream of tau pathology and neurodegeneration. However, our
understanding of plaque diversity and how this relates to NFTs has remained limited. Notably, the relevance of
Aβ and amyloid plaques in AD has seen a recent resurgence in FDA approvals and activities. For example, the
FDA recently approved aducanumab that can remove amyloid plaques as measured by positron-emission
tomography. Although the importance of amyloid plaques in AD have long been recognized, exactly how
plaques develop over time, the extent of their diversity, and their relationship to NFTs is not well understood.
Therefore, it is of great importance to map the trajectory of distinct classes of amyloid aggregates in brains with
amyloid or both amyloid and NFT pathology.
 The project leaders recently discovered several important and early events in the formation of
Aβ plaques in AD model brains and have developed several new approaches to study these processes. First,
we discovered that impaired protein homeostasis in axon terminals represents a pioneering synaptic defect in
mice modeling the early stage of amyloid pathology in AD. Second, we found that proteins localizing to axon
terminals have selectively hampered turnover through plaque dependent and independent mechanisms. Third,
formation of structurally distinct plaques are associated with differential Aβ peptide deposition. Finally, Aβ42
comprises the initial core structure followed by radial outgrowth and later incorporation of Aβ38. To rigorously
extend these findings, in Aim 1 we will deeply characterize amyloid plaque diversity in mouse model brains.
The goal of Aim 2 is to determine how the presence of NFTs influence amyloid plaque dynamics. The
proposed research will advance our understanding of AD by characterizing amyloid plaques based on
aggregation kinetics, what structural Aβ assemblies are formed, how these oligomers and plaques trigger
mechanisms leading to downstream synaptic dysfunction, and how these properties of amyloid plaques are
modulated by NFTs.

## Key facts

- **NIH application ID:** 10754960
- **Project number:** 5R21AG080705-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Jorg Hanrieder
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $170,112
- **Award type:** 5
- **Project period:** 2022-12-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10754960

## Citation

> US National Institutes of Health, RePORTER application 10754960, Insights into Amyloid Pathogenicity Dynamics (5R21AG080705-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10754960. Licensed CC0.

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