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Multifaceted approaches modulate slow-wave activity as therapeutic interventions in mouse models of Alzheimer's disease: Drug-free therapy, pharmaceutical therapy and gene-therapy

Award Number: R56AG098813
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: 08/31/2027

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Multifaceted approaches modulate slow-wave activity as therapeutic interventions in mouse models of Alzheimer's disease: Drug-free therapy, pharmaceutical therapy and gene-therapy - Alzheimer’s Disease (AD) is a devastating illness increasing in prevalence with no cure. In the last 12 years, basic and clinical work has revealed deep sleep washes the brain of toxins that cause AD. Electroencephalographic (EEG) brain waves that define deep sleep – “slow-wave activity” – precede, possibly coordinate, cerebrospinal fluid (CSF) washes promoting brain clearance. Yet, slow-wave activity has not been a major target for AD therapy. Slow-wave activity is regulated by circuits that connect the thalamus and the cortex; and by the claustrum, a thin long well-connected region enriched with the carboxypeptidase inhibitor called latexin. Slow-wave activity, the claustrum and latexin are all reduced in AD. This translational proposal in AD model mice is comprised of three independent specific aims, each using distinct methodologies to bolster slow-wave activity. Aim 1) Acoustic stimulation at the slow-wave frequency during wakefulness. Aim 2) Pharmaceutical targeting of brain circuits generating slow-wave activity. Aim 3) Chemogenetic modulation and gene-therapy of the claustrum. In each aim we will assess the effectiveness of these interventions to 1) increase brain clearance, 2) reduce amyloid-β (Aβ) deposits in brain tissue, 3) improve cognitive performance on behavioral tasks. Our preliminary data demonstrate feasibility and likelihood of successfully completing this project: 1) Our ability to measure EEG and brain clearance simultaneously in vivo, in real time, and repeatedly, during records lasting >24h. 2) Our ability to use an innovative acoustic stimulation to bolster slow-wave activity during wakefulness, and reduce Aβ in AD mice. 3) Our ability to bolster slow-wave activity during non- REM by a pharmaceutical called α3IA in AD mice. 4) Resources to rigorously test the hypothesis that α3IA bolsters slow-wave activity by stimulating the neurocircuits generating slow-wave activity. 5) Selective stimulation of the claustrum by the excitatory chemogenetic construct hM3Dq to boost slow-wave activity. 6) Our ability to design and acquire novel gene-therapy based constructs for expressing latexin selectively in the claustrum. 7) Our ability to bolster slow-wave activity with gene-therapy mediated expression of latexin in the claustrum of AD mice. Each aim develops interventions that can be translated as therapies for AD. Aim 1 focuses on a cheap, scalable and non-invasive method for use in patients’ homes. Aim 2 focuses on a drug with well-established molecular mechanisms which could enter clinical trials. Aim 3 uses gene therapy-based technologies to provide an avenue to treatment for those at high risk of AD. We also describe early markers preceding symptoms in AD mice, which could lead to screens for high risk of AD.


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 = $617,796 )
2026	2026	BOSTON VA RESEARCH INSTITUTE, INC.	2 AVENUE DE LAFAYETTE	BOSTON	MA	02111	SUFFOLK	USA	Aging Research	000	1	9/9/2026	NEW	$617,796
														Subtotal = $617,796

Grand Total All Awards = $617,796

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Multifaceted approaches modulate slow-wave activity as therapeutic interventions in mouse models of Alzheimer's disease: Drug-free therapy, pharmaceutical therapy and gene-therapy

Award Number: R56AG098813

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: 08/31/2027

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