# Alpha-synuclein aggregate induced synapse loss is a pathological event contributing to Lewy body dementias

> **NIH NIH R56** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $768,806

## Abstract

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), collectively called Lewy body
dementias (LBDs), are the second most common cognitive disorder after Alzheimer's disease (AD). Patients
with LBDs suffer from PD-related motor defects and deficits in executive dysfunction, attention, and
visuospatial processing, reflective of cortical dysfunction. Pathologically, LBDs are characterized by abundant
cortical aggregates of α-synuclein (α-syn) called Lewy pathology (LP). The cognitive impairments in LBDs are
the main cause for institutionalization and mortality. There are no treatments that halt the progression of LBDs.
Outstanding scientists in the field of LBDs have provided data supporting that the combination of Lewy
pathology and aggregates of tau, similar to those found in Alzheimer's disease, together are strongly
associated with reduced performance on cognitive tasks. In Alzheimer's disease, loss of synapses is the
strongest correlate of cognitive decline. Recently evidence has emerged from several labs, including ours,that
synapse loss in the cortex may contribute to cognitive changes in LBDs. We propose that the presence of both
alpha-synuclein and tau aggregates at the synapse synergistically contributes to synapse degeneration in
LBDs. We propose the interaction of α-syn and tau at the presynaptic terminal induces synapse degeneration.
This proposal will combine the expertise of multiple investigators to test whether 1) the interaction of alpha-
synuclein and tau facilitates synapse degeneration and 2) whether presynaptic terminals with small aggregates
of both alpha-synuclein and tau show enhanced degeneration in the prefrontal cortex of patients that suffered
from Lewy body dementias. We will use novel antibodies that selectively detect oligomeric and pathologic
conformation of alpha-synuclein and tau. We will use a novel super-resolution technique called Expansion
Microscopy (ExM) that can rapidly and quantitatively provide nanoscale resolution of synapses. We will also
use a novel antibody multiplexing technique that can amplify low-abundance synaptic signals and allow
imaging of >5 proteins at once. The results of this proposal will move the field of LBDs forward by 1) beginning
to elucidate the mechanisms that contribute to synapse loss and cognitive changes in LBDs, and 2) identify if
targeting the alpha-synuclein/tau interaction prevents synapse loss and cognitive decline.

## Key facts

- **NIH application ID:** 10204271
- **Project number:** 1R56NS117465-01
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Laura A. Volpicelli-Daley
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $768,806
- **Award type:** 1
- **Project period:** 2020-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10204271

## Citation

> US National Institutes of Health, RePORTER application 10204271, Alpha-synuclein aggregate induced synapse loss is a pathological event contributing to Lewy body dementias (1R56NS117465-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10204271. Licensed CC0.

---

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