# Seizure-induced enhancement of synaptic signaling regulating tau transmissibility in Alzheimer's Disease

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $712,374

## Abstract

Abstract
Alzheimer’s Disease (AD) neuropathology is largely driven by two pathological AD proteins, tau,
and ß-amyloid (Aß), both of which induce neuronal hyperexcitability and are thought to play a role
in the high comorbidity between AD and epilepsy. Tau load and its regional brain distribution
correlate more closely with cognitive decline than amyloid plaque deposition in both AD and
epilepsy patients, making tau an attractive target for disease modification in both conditions. AD
patients have an increased incidence of epilepsy compared to non-AD patients, and we recently
showed that kindled seizures can exacerbate amyloid pathology, mediated by the mammalian
target of rapamycin complex 1 (mTORC1) activation in an AD mouse model. To address how
neuronal hyperactivity can increase AD pathology, we propose to use a tau seeding approach
using two novel AD mice models to determine the effects of later seizures on the spatiotemporal
accumulation of pathologic tau. We will also test the hypothesis that tau transmissibility in AD
occurs through synaptic activation by adapting a method to permanently label cells activated by
kindled seizures following tau seeding. This will allow us to measure the levels and spatial and
temporal distribution of tau and AD pathology throughout the entire brain, as well as gene and
protein expression at single neuron level. We will also utilize human brain tissue from AD patients
with and without a seizure history, and controls, to validate molecular changes observed in the
mouse models. Finally, given our prior observations regarding the therapeutic effects of
rapamycin, and the hypothesis that tau accumulation and transmission is accelerated by seizures,
we will use the two tau seeding mouse models to assess the therapeutic efficacy of post-seizure
chronic treatment with the mTORC1 inhibitor rapamycin or the antiseizure drug levetiracetam in
attenuating AD progression.

## Key facts

- **NIH application ID:** 10837726
- **Project number:** 5R01AG077692-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Frances E Jensen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $712,374
- **Award type:** 5
- **Project period:** 2022-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10837726

## Citation

> US National Institutes of Health, RePORTER application 10837726, Seizure-induced enhancement of synaptic signaling regulating tau transmissibility in Alzheimer's Disease (5R01AG077692-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10837726. Licensed CC0.

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