# Understanding Amyloid Pathology - Multiomic Activity Imaging of Plaque Formation Dynamics (AmyMAP)

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2022 · $579,740

## Abstract

ABSTRACT
 Alzheimer's disease (AD) is an incurable brain disorder that currently debilitates more than five million
people in the United States alone. Clinically, AD typically presents as a slow and progressive decline in
cognitive performance that inevitably culminates in severe dementia. Currently AD can only be positively
confirmed postmortem by dementia with amyloid beta (Aβ) peptides plaques and neurofibrillary tangles
containing the hyper-phosphorylated Tau protein. It is generally accepted that plaques and tangles play
important and complex roles in AD. The prevailing model of AD pathogenesis has been that changes in Aβ
metabolism precipitate a damaging cascade upstream of tau pathology and eventual neurodegeneration.
However, there is a lot about these enigmatic pathological marks that we do not understand. 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 the amyloid plaques in AD have long been recognized, exactly how
plaques develop over time, the extent of their diversity, and their relation to toxic or homeostatic response of
the surrounding neuronal circuits remains unclear. Therefore, it is of great importance to map the trajectory of
distinct classes of amyloid aggregates during the early stages of A pathology.
 We have recently discovered several important and early events in the formation of A 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 amyloid model mice.
Second, we found that the synaptic vesicle release and recycling machinery has 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 obtain a
dynamic map of amyloid plaque pathology in mouse model brains during aging. The goal of Aim 2 is to
determine how the AD risk factor Trem2 influences A, lipid, and protein dynamics at amyloid plaques. In Aim
3, we will integrate the multi-omic amyloid maps with measures of altered synaptic communication and
neurotoxicity. Finally, in Aim 4, we apply the knowledge gained in a practical manner with 3D mapping for the
neuroscience research community. The proposed research will advance our understanding of AD by
determining when Aβ is aggregating in the extracellular space, what structural Aβ assemblies are formed, and
how these oligomers and plaques trigger mechanisms leading to downstream synaptic dysfunction.

## Key facts

- **NIH application ID:** 10516489
- **Project number:** 1R01AG078796-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Jorg Hanrieder
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $579,740
- **Award type:** 1
- **Project period:** 2022-09-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10516489

## Citation

> US National Institutes of Health, RePORTER application 10516489, Understanding Amyloid Pathology - Multiomic Activity Imaging of Plaque Formation Dynamics (AmyMAP) (1R01AG078796-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10516489. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*