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Deciphering the Role of Noradrenergic Receptors during Neuromodulation in Alzheimer's Disease

Award Number: K00AG084261
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Deciphering the Role of Noradrenergic Receptors during Neuromodulation in Alzheimer's Disease - PROJECTIVE SUMMARY Alzheimer’s disease (AD), characterized by abnormal accumulation of amyloid plaques and neurofibrillary tangles within the brain, is the most common form of dementia for adults aged 65 and up and the 7th leading cause of death worldwide. Despite initial diagnoses of AD occurring over a century ago, effective clinical therapies to prevent or treat disease progression are currently lacking. The locus coeruleus (LC), an important brainstem nuclei which acts as the primary source of norepinephrine (NE) throughout the brain, has been identified as one of the earliest structures to deteriorate in AD. LC degeneration is strongly correlated with severity of cognitive decline, suggesting strategies to preserve or enhance LC function offer significant therapeutic potential. Furthermore, NE potentiates established anti-inflammatory properties and is known to induce microglia phagocytosis and clearance of amyloid in AD. Therefore, promoting NE release via LC stimulation is an emerging strategy to alleviate neuropathology and cognitive deficits in AD. However, the molecular and cellular processes which govern the potential therapeutic effects of the LC-NE system during AD progression remain unknown. This K00 research strategy proposes a multi-modal approach involving gene editing, intravital imaging, electrophysiology, behavioral training, and single cell sequencing to reveal the functional role of cell-type and sub-type specific noradrenergic receptors during LC stimulation in AD. In Aim 1, a baseline will be established determining the extent in which long-term LC stimulation reduces neuroinflammation, amyloid/tau burden, and cognitive impairment in two different rodent models of AD. In Aim 2 and 3, gene editing will be used to interfere with sub-type specific noradrenergic receptors in astrocytes and microglia, respectively, to understand both cell-type and sub-type specific contributions of noradrenergic receptors on therapeutic outcomes in neuropathology and cognitive performance following long-term LC stimulation in AD. Neuroinflammatory profiles within individual cell populations will be assessed using single cell RNA sequencing while morphological and functional changes will be tracked longitudinally using two-photon microscopy. Alterations in disease neuropathology following long-term LC stimulation will be compared to changes in neuronal electrophysiology and cognitive performance over time. Ultimately, the outcomes of this proposal will overcome significant knowledge barriers surrounding how LC stimulation rescues AD symptoms and highlight novel biological targets to enhance therapeutic efficacy of neuromodulatory drugs and devices for disease therapy.


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 = $0 )
2026	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	615 W 131ST ST	NEW YORK	NY	10027	NEW YORK	USA	Aging Research	000	4	11/25/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	615 W 131ST ST	NEW YORK	NY	10027	NEW YORK	USA	Aging Research	000	4	5/28/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $91,963 )
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	615 W 131ST ST	NEW YORK	NY	10027	NEW YORK	USA	Aging Research	000	4	3/21/2024	NON-COMPETING CONTINUATION	$91,963
														Subtotal = $91,963

Issue Date FY: 2023 ( Subtotal = $84,624 )
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	202 LOW LIBRARY 535 W 116 ST MC 4309,	NEW YORK	NY	10027	NEW YORK	USA	Aging Research	001	3	9/21/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	202 LOW LIBRARY 535 W 116 ST MC 4309,	NEW YORK	NY	10027	NEW YORK	USA	Aging Research	000	3	3/20/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$84,624
														Subtotal = $84,624

Grand Total All Awards = $176,587

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Deciphering the Role of Noradrenergic Receptors during Neuromodulation in Alzheimer's Disease

Award Number: K00AG084261

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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