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Role of Brain Aromatase in Alzheimer's Dementia: Sex differences and the Preventive Therapy using Pulsed Photobiomodulation

Award Number: R01AG083947
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/25/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Role of Brain Aromatase in Alzheimer's Dementia: Sex differences and the Preventive Therapy using Pulsed Photobiomodulation - Abstract Alzheimer's disease (AD) is a growing global health concern that disproportionately impacts women. Additionally, patients with aromatase/estrogen receptor inhibitors often experience cognitive decline. However, the underlying pathophysiology and sexual dimorphic mechanisms are still not completely understood, and no proven treatment or prevention is currently available. Our preliminary studies suggest that brain aromatase/17β-estradiol (E2) declines significantly preceding the symptoms of AD dementia in rodent AD models, and systemically inhibiting aromatase or brain-specific knockdown of aromatase further aggravates AD progression, especially in females. Conversely, the retention of brain aromatase/E2 using exogenous E2 administration or pulsed photobiomodulation (PBM)/laser treatment can mitigate AD development and alleviate cognitive impairment. Therefore, this proposal aims to elucidate the role of brain aromatase in AD development and identify whether aromatase is a new target for PBM therapy for preventing and managing AD. Our central hypothesis is that a decline in brain aromatase plays a causal role in the pathogenesis of AD and that pulsed PBM can target the heme-iron-containing aromatase enzyme to improve its activity and preserve local brain E2 level, thereby promoting synaptogenesis and ameliorating cognitive decline in AD. To test these hypotheses, we will first examine whether downregulation or inhibition of aromatase is associated with aggravated cognitive decline and if PBM or E2 treatment prevent aromatase decline and cognitive deficits in a novel AD rat model. Secondly, we will test if brain aromatase mediates the beneficial effects of PBM therapy on local E2 production and cognitive improvements using different AD models. Third, we will determine if PBM enhances synaptogenesis and spine formation via an aromatase/E2-irisin-BDNF signaling mechanism in both in vivo and in vitro AD models. To accomplish our objective, we will use transgenic TgF344-AD and 3xTg-AD rodent models, forebrain neuron-specific aromatase KO (FBN-Aro-KO) mice, and cross-generated FBN-Aro-KO AD mice. Rat primary neuronal cultures exposed to PBM will also be employed to validate our hypothesis. Our proposed research is both mechanistically and technically innovative as it will elucidate the efficacy of pulsed PBM therapy in retaining brain aromatase/E2 homeostasis in different AD models while also identifying novel signaling mechanisms for pulsed PBM therapy. In addition, our proposed research could offer an important adjuvant therapy for patients with aromatase/estrogen receptor inhibitors. Therefore, this proposal has valuable clinical novelty for the prevention and management of AD dementia and to explain the sex differences in AD development.


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: 2025 ( Subtotal = $754,578 )
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	002	2	8/21/2025	NON-COMPETING CONTINUATION	$754,578
2025	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	000	1	11/20/2024	NEW	$0
2025	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	001	1	4/28/2025	NEW	$0
														Subtotal = $754,578

Issue Date FY: 2024 ( Subtotal = $769,978 )
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Aging Research	000	1	9/24/2024	NEW	$769,978
														Subtotal = $769,978

Grand Total All Awards = $1,524,556

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Role of Brain Aromatase in Alzheimer's Dementia: Sex differences and the Preventive Therapy using Pulsed Photobiomodulation

Award Number: R01AG083947

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/25/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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