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A novel strategy to reverse neural hyperexcitability in Alzheimer's disease

Award Number: R01AG099117
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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A novel strategy to reverse neural hyperexcitability in Alzheimer's disease - Alzheimer’s disease (AD) is the most common form of dementia with no known cause and cure. Emerging evidence shows that hippocampal hyperexcitability is a common functional feature of AD that is associated with greater AD pathology and cognitive decline. Thus, hyperexcitability in the hippocampus could be a potential target for both symptomatic and disease-modifying therapies. However, our current knowledge of hyperexcitability in AD is far from complete. Specifically, there is still much to learn about the hippocampal circuits that are affected in AD, their composite cell types, and the mechanistic link between hyperactivity, pathology, and cognitive impairment. The significance of the proposed work is thus predicated on filling these knowledge gaps, which is essential for the development of novel treatment strategies for AD. Research suggests that beta- amyloid peptide (Aβ)-induced reduction of hippocampal inhibition is a crucial trigger for cognitive impairment and amyloid pathology in AD via hyperexcitability. Therefore, enhancing hippocampal inhibition is thought to be neuroprotective against AD. However, hippocampal inhibitory cells are highly diverse, and these distinct interneuron subtypes differentially regulate hippocampal inhibitory circuits and cognitive processes. Moreover, Aβ unlikely affects all subtypes of inhibitory interneurons in the hippocampus equally. Hence, identifying the affected interneuron subtypes in AD to enhance hippocampal inhibition optimally is conceptually and practically challenging. Our published works have demonstrated that Aβ selectively binds to two of the three major hippocampal nicotinic acetylcholine receptor (nAChR) subtypes, α7- and α4β2-nAChRs, but not α3β4-nAChRs, and inhibits these two receptors in cultured hippocampal parvalbumin-positive (PV+) and somatostatin-positive (SST+) inhibitory interneurons, respectively, to decrease their activity, leading to hyperexcitation and synaptic dysfunction in cultured hippocampal excitatory neurons. We have also revealed that co-activation of α7- and α4β2-nAChRs is required to reverse the Aβ-induced adverse effects in cultured neurons. We thus hypothesize that co-stimulation of PV+ and SST+ cells via activation of α7- and α4β2-nAChRs together is required to enhance hippocampal inhibition optimally, which reverses hippocampal dysfunction, reduces amyloid pathology, and ultimately prevents memory loss in AD. We will use hippocampal slices and two widely used amyloid pathology mouse models examine whether Aβ reduces hippocampal inhibition via decreasing cholinergic activity in inhibitory interneurons in hippocampal slices (Aim 1), to examine whether co-stimulation of PV+ and SST+ interneurons reduces hippocampal hyperexcitability in AD model mice (Aim 2), to address if co-activation of α7- and α4β2-nAChRs improves memory consolidation-associated hippocampal network activity in AD model mice (Aim 3), and to examine if intrahippocampal nAChR activation is sufficient to improve memory (Aim 4).


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $633,758 )
2026	2026	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	Aging Research	000	1	9/11/2026	NEW	$633,758
														Subtotal = $633,758

Grand Total All Awards = $633,758

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A novel strategy to reverse neural hyperexcitability in Alzheimer's disease

Award Number: R01AG099117

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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