# Hyperexcitability in Alzheimer's Disease

> **NIH NIH R01** · NATHAN S. KLINE INSTITUTE FOR PSYCH RES · 2021 · $404,250

## Abstract

ABSTRACT
 It has been suggested that neuronal hyperexcitability is an important characteristic in Alzheimer’s
disease (AD) because it contributes to the impairment in memory and increasing levels of amyloid
β (Aβ) that characterize the disease. Using animal models of AD neuropathology we suggest that the
most common form of hyperexcitability is a synchronized spike in hippocampus and cortical neurons
that is similar to the spikes between seizures in epilepsy, called interictal spikes (IIS). Our data
suggests that IIS occur very early and are very common, yet seizures are rare. Therefore we have a
potential opportunity to characterize a novel biomarker, IIS, and clarify the relationship between
hyperexcitability and AD.
 Preliminary data have primarily used a mouse model where the precursor to amyloid precursor
protein (APP), the precursor to Aβ is mutated to simulate a Swedish family with familial AD, and
expressed widely in the brain.  By 5 weeks of age, months before Aβ deposition, we have found IIS as
the animals are sleeping. With age the animals develop frequent IIS that occur in other brain states
besides sleep and there are also memory impairments and plaque formation. In other animal models
IIS also occur, yet seizures are rare. When examining the brains of the young mice we find that the
basal forebrain (BF) cholinergic neurons and dentate gyrus granule cells show signs of elevated
activity, instead of hypoactivity that characterizes the brain at older ages. We suggest that BF
cholinergic neurons stimulate the granule cells and this leads to synchronized action potentials. In
support, the muscarinic cholinergic antagonist atropine reduces the IIS in sleep, as well as in vitro
measurements in hippocampal slices that we think reflect the abnormal activity. We now propose
experiments to test these hypotheses with multiple methods including viral-mediated silencing of
cholinergic neurons in vivo.
 In the last part of the proposal we will examine two strategies that our pilot experiments show can
reduce IIS to determine if cognition and neuropathology are ameliorated. One of these has already
been tested in a mouse model of Down’s syndrome, a condition where AD is prevalent: maternal
choline supplementation. The second, a reduction of the neurotrophin receptor p75 (p75NTR), has
been tested in one of the mouse models we will use, the Tg2576 mouse, and it is already known that
it ameliorates memory impairments in the mice. In summary, this project will address an area of AD
research which has been difficult to clarify and controversial: hyperexcitability in AD. We suggest that
there are early signs of hyperexcitability, IIS, that present opportunities for better mechanistic
understanding and intervention.

## Key facts

- **NIH application ID:** 10135793
- **Project number:** 5R01AG055328-05
- **Recipient organization:** NATHAN S. KLINE INSTITUTE FOR PSYCH RES
- **Principal Investigator:** Helen E Scharfman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $404,250
- **Award type:** 5
- **Project period:** 2017-04-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10135793

## Citation

> US National Institutes of Health, RePORTER application 10135793, Hyperexcitability in Alzheimer's Disease (5R01AG055328-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10135793. Licensed CC0.

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