# Shedding light on functional heterogeneity of dementia-related alpha-synuclein strains

> **NIH NIH R21** · UNIVERSITY OF MARYLAND BALTIMORE · 2022 · $463,124

## Abstract

The deposition of α-synuclein (αS) in the brain is a main feature of Lewy bodies dementia (LBD), which is the
2nd most common dementia after Alzheimer’s disease (AD). Both postmortem and experimental evidence
showed that the progression of LBD can be driven by pathogenic αS (preformed fibrils, PFF) in a prion-like
fashion, and these αS aggregates exhibit distinct strains underling heterogeneity of α-synucleinopathies. In our
preliminary studies, we have amplified αS aggregates from patients and found the strains from Parkinson's
disease with cognitive impairment (PD-CI) are distinct from those derived from PD with normal cognition (PD-
NC) in the cross-sectional analysis. Longitudinal studies of αS strains from the same individuals further indicate
a strain conversion when cognition progresses from PD-NC to PD-CI. However, there are two critical knowledge
gaps in the current understanding of the heterogeneity of αS strains. First, whether and how distinct αS strains
cause different cellular responses in the brain of a living organism are poorly known. It is our vision that
interdisciplinary efforts are essential to bring novel insights on the pathogenesis of LBD. We have established
the long-term intravital single-cell tracking platform under 2p microscopy, enabling subcellular-resolution imaging
of the location, migration, and function of brain cells in live mice for a few weeks. Implementing this tool allows
us to address the above-mentioned question by obtaining a dynamic picture about how brain cells respond to
αS over time, including temporal responses from neurons and microglia exposed to different strains of αS. The
second critical knowledge gap is whether different strains of αS have distinct cell-to-cell propagation dynamics.
The gold standard histological methodology for α-synucleinopathies is the immunoreactivity of posttranslational
phosphorylation of αS at serine 129 (p129), precluding the possibility to obtain dynamic αS propagation
information. To address this issue, we propose to design a novel probe for αS, called the NanoFAST, which has
a few inherent advantages over other αS aggregation reporters: (i). detection of untagged αS aggregates; (ii).
no need to overexpress αS in cells for the reporter to work; and (iii). the ability to detect either aggregation or
disaggregation (bi-directional) process of αS. Overall, we have assembled an interdisciplinary team covering
neuroscience, nanobody engineering, biophysics, and clinical practice to address the critical knowledge gaps in
the understanding of αS heterogeneity. If we are successful, the long-term intravital cell tracking of the response
of neurons/microglia to different αS strains will provide important insights on the mechanism underlying
heterogeneity in neurotoxicity from dementia-related αS strains. The NanoFAST may become an enabling tool
for exploring αS aggregating and spreading dynamics in cell-based assay or even for in vivo applications, with
the potential to be tra...

## Key facts

- **NIH application ID:** 10447375
- **Project number:** 1R21AG077631-01
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Yajie Liang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $463,124
- **Award type:** 1
- **Project period:** 2022-08-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10447375

## Citation

> US National Institutes of Health, RePORTER application 10447375, Shedding light on functional heterogeneity of dementia-related alpha-synuclein strains (1R21AG077631-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10447375. Licensed CC0.

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