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Respiratory dysfunction in Alzheimer's disease and its link to oxidative damage within the brain stem.

Award Number: R15AG065927
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Respiratory dysfunction in Alzheimer's disease and its link to oxidative damage within the brain stem. - PROJECT SUMMARY/ABSTRACT: The majority of Alzheimer's disease (AD) patients exhibit respiratory dysfunction that can lead to poor quality of life and various health complications. There is no cure and mechanisms behind these changes are unknown. AD pathology affects the entire brain, including brainstem centers important for respiration. Within the brainstem, the nucleus tractus solitarii (nTS) is essential in respiratory control and AD patients show clear pathological alterations in the nTS similar to those seen in memory-related brain structures of the forebrain. Furthermore, reactive oxygen species (ROS) are tightly associated with the etiology of AD and ROS within the nTS critically alter neuronal function. However, the consequences of ROS and altered nTS activity for respiratory dysfunction in Alzheimer's disease are unknown. By using a model that closely mimics human AD and the associated respiratory dysfunction, this study will focus on altered nTS processing in respiratory control and examine the underlying neurophysiological mechanisms. Current AD treatments using antioxidants to decrease ROS load are failing in AD patients. While excessive ROS can be removed, the oxidative damage prevails and continues to induce AD symptoms. Specific sub-cellular targets of ROS have not been examined yet. Our central HYPOTHESIS is that ROS- induced augmented nTS-activity underlies respiratory dysfunction in AD and that repair of oxidative damage in addition to lowering ROS is needed for effective treatment of respiratory dysfunction in Alzheimer's disease. This hypothesis will be addressed by determining the morphological, functional, and mechanistic alterations within the chemosensitive nTS in Alzheimer's disease (AIM 1). We will examine the nTS in regard to changes in major cell types, chemosensory terminals, candidate AD markers, and basal activity when inflicted with AD. To analyze the functional role of the nTS in AD, we will pharmacologically alter nTS activity (using microinjections into the nTS) and monitor respiratory output using in vivo electrophysiological recordings in anesthetized rats. The neurophysiological mechanisms behind these alterations will be addressed with in vitro patch clamp recordings in nTS slices. Changes in chemoafferent synaptic input, nTS neuronal properties, and underlying ionic currents in AD will be examined. We will also identify ROS-induced damage within the nTS in AD (AIM 2). ROS levels, antioxidant defense systems, and oxidation state of the nTS will be analyzed. The particular role of AD-derived ROS in the nTS will be examined by local upregulation of antioxidants in the nTS. Functional implications of chronic AD-ROS and their removal (similar to current therapeutic strategies) will be identified using acute nTS microinjections of antioxidants. Acute rescue of ROS-sensitive targets will then elucidate the contribution of oxidative damage to respiratory dysfunction in AD. Our study will be the first to address the mechanistic origin of life-threatening respiratory complications with AD. Our results will likely facilitate development of novel strategies targeting ROS-induced damage in AD to improve respiratory health.


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 = -$104 )
2025	2021	A. T. STILL UNIVERSITY OF HEALTH SCIENCES	800 W JEFFERSON ST	KIRKSVILLE	MO	63501	ADAIR	USA	Aging Research	000	1	5/1/2025	NEW	-$104
														Subtotal = -$104

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	A. T. STILL UNIVERSITY OF HEALTH SCIENCES	800 W JEFFERSON ST	KIRKSVILLE	MO	63501	ADAIR	USA	Aging Research	000	1	1/19/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $387,403 )
2021	2021	A. T. STILL UNIVERSITY OF HEALTH SCIENCES	800 W JEFFERSON ST	KIRKSVILLE	MO	63501	ADAIR	USA	Aging Research	000	1	2/12/2021	NEW	$387,403
														Subtotal = $387,403

Grand Total All Awards = $387,299

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Respiratory dysfunction in Alzheimer's disease and its link to oxidative damage within the brain stem.

Award Number: R15AG065927

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/15/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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