# Recovery of Synaptic Dysfunction and Memory Loss in Alzheimer's Disease by Selective Co-Activation of Nicotinic Acetylcholine Receptors

> **NIH NIH R03** · COLORADO STATE UNIVERSITY · 2022 · $152,000

## Abstract

Many studies have provided evidences that beta-amyloid peptide (Aβ) triggers synaptic dysfunction and
loss of hippocampus-dependent memory in the prodromic stage of Alzheimer’s disease (AD), but the underlying
mechanisms remain uncertain. Aβ can alter neuronal signaling through interactions with nicotinic acetylcholine
receptors (nAChRs), which elicits synaptic dysfunction in AD. Indeed, the loss of nAChRs is the prominent AD
pathology, thus Aβ-induced disruptions of nAChR function underlie deficits in hippocampal synapses, leading to
memory loss in AD. However, the effect of Aβ on nAChR physiology is complex - Aβ can act like an agonist or
an antagonist on the receptors. Significantly, most of currently prescribed drugs for AD inhibit the general
breakdown of acetylcholine (acetylcholinesterase inhibitors), thus potentially stimulates all types of acetylcholine
receptors. Importantly, they have only modest efficacy due to non-selective stimulation of acetylcholine receptors
given that nearly 30 subtypes of neuronal nAChRs have been reported in the human brain. This suggests distinct
nAChR subtypes are differentially affected in AD. Among the three major nAChR subtypes in the hippocampus,
α7-, α4β2-, and α3β4-nAChRs, we identify that Aβ selectively affects α7- and α4β2-nAChRs together, but not
α3β4-receptors, in cultured mouse hippocampal neurons, resulting in neuronal and synaptic dysfunction, an
important characteristic in AD. Moreover, we reveal that selective co-activation of α7- and α4β2-receptors is
sufficient to reverse the Aβ effects in cultured hippocampal neurons. Therefore, the overall hypothesis of the
proposed work is that selective co-activation of α7 and α4β2 nAChRs reverses Aβ-induced synaptic dysfunction
and memory loss in AD. However, isolated neurons do not reflect the nature of the organism due to the isolation
and lack of contact with other cells. The significance of the proposed work thus is based on the scientific premise
that further studies using intact neural circuits are needed in order to investigate nAChR subtype selectivity of
Aβ effects on synaptic function and memory in AD. In the proposed work, we will thus use brain slice
electrophysiology and animal behavioral assays to test our hypothesis. Moreover, we will use Tg2576
transgenic mice, one of the most well characterized, and widely used, mouse models of AD. In Aim 1. we will
test the hypothesis that selective co-activation of α7- and α4β2-nAChRs reverses Aβ-induced altered synaptic
plasticity. In Aim 2, we will determine the hypothesis that selective co-activation of α7- and α4β2-nAChRs
improves learning and memory in AD model mice. Given that cholinergic deficiency is associated with AD,
strategies aiming to restore normal cholinergic function have been developed as therapeutic drugs for AD.
Unfortunately, no nAChR compounds have demonstrated disease-modifying properties for AD so far. Therefore,
the idea that selective co-activation of α7- and α4β2-nAChRs in t...

## Key facts

- **NIH application ID:** 10468170
- **Project number:** 5R03AG072102-02
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** Seonil Kim
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $152,000
- **Award type:** 5
- **Project period:** 2021-08-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10468170

## Citation

> US National Institutes of Health, RePORTER application 10468170, Recovery of Synaptic Dysfunction and Memory Loss in Alzheimer's Disease by Selective Co-Activation of Nicotinic Acetylcholine Receptors (5R03AG072102-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10468170. Licensed CC0.

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