# Alpha-Synuclein Induced Network Hyperexcitability in Lewy Body Dementias

> **NIH NIH R56** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $840,282

## Abstract

PROJECT SUMMARY
Lewy body dementias (LBD), including Parkinson’s disease dementia (PDD) and dementia with Lewy bodies
(DLB), are the second most common type of degenerative dementia in the world. Unfortunately, there are
currently no therapies to slow or halt the progression of LBD. Seizures associated with LBD deserve more
attention because, despite the harmful impact on the patients, seizure activity can go unrecognized and
untreated. Seizures or myoclonus occur in over half of DLB patients, and these symptoms hasten cognitive
decline. Our preliminary studies indicate that abnormal α-synuclein (αS), a key component of Lewy bodies,
causes cognitive deficits preceded by epileptic activity. We also show that αS-dependent synaptic and cognitive
deficits and epileptic activity require endogenous tau expression. This is reminiscent of data showing that the
tau-dependence of cognitive deficits and epileptic activity in the mouse models of Alzheimer’s disease (AD).
Preventing epileptic activity with antiseizure drugs improves memory in models of AD, and antiseizure drugs are
currently in early phase clinical trials for AD. However, antiseizure drugs have not been well investigated for α-
synucleinopathy. To better define the role of seizure activity in LBD, the following aims are proposed: Aim 1,
Determine the causal relationship between the epileptiform activity and αS-dependent cognitive deficits; Aim 2,
Determine if αS fibril inoculation model of PDD/DLB causes tau-dependent cognitive deficits mediated by
epileptiform activity; and Aim 3, Define the circuitry and cellular signaling mechanisms contributing to epileptiform
activity in mutant αS models. The results of this investigation could lead to new strategies, such as antiseizure
drugs and reducing tau levels, as therapies for LBD.

## Key facts

- **NIH application ID:** 10470990
- **Project number:** 1R56AG074473-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** MICHAEL K LEE
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $840,282
- **Award type:** 1
- **Project period:** 2021-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10470990

## Citation

> US National Institutes of Health, RePORTER application 10470990, Alpha-Synuclein Induced Network Hyperexcitability in Lewy Body Dementias (1R56AG074473-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10470990. Licensed CC0.

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