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Proteostasis dysregulation and the development of Alzheimer's-like neurodegeneration and dementia in Down syndrome

Award Number: R01AG080817
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Proteostasis dysregulation and the development of Alzheimer's-like neurodegeneration and dementia in Down syndrome - Down syndrome (DS) is a congenital condition resulting from partial or complete triplication of human chromosome 21. Virtually all the subjects with DS develop widespread neuropathology including amyloid- neuritic plaques, synaptic dysfunction and neurodegeneration, reminiscent of Alzheimer's disease. While the extra copy of amyloid- precursor protein (APP) on chromosome 21 is thought to play a major role in the development of this type of pathologic phenotype in DS, the underlying mechanisms responsible for these changes and their contribution to neurodegeneration are still elusive. Compelling evidence supports the hypothesis that physiological cellular proteostasis is of critical importance for neuronal health and that the mammalian target of rapamycin (mTOR) is a master regulator of this vital cellular function. However, while we know that the system is altered in DS we do not know whether it plays a functional role in the pathogenesis of DS and the onset of neuropathology. In our preliminary data we found that compared with healthy matched controls mTOR is hyperactive in selected brain regions of DS patients. Importantly, we observed that in the same subjects the dysfunction directly correlates with the pathology. Moreover, we show that mTOR is altered in the brain of a well- established mouse model of DS, the Ts65Dn mice, at an early stage of the phenotype, and associates with biochemical evidence of cell loss, suggesting a link between mTOR, neuropathology and neurodegeneration in DS subjects. Taking into consideration the scientific rigor of the previously published literature together with our recent findings we now propose a novel working hypothesis: alteration of mTOR signaling pathway is responsible for the onset of the neuropathologic DS phenotype and represents a novel and viable therapeutic target against it in DS subjects. In this proposal, we will assess the temporal relationship between dysregulation of mTOR in the brain of DS patients and the development of the neuropathology. We will then focus on investigating early events responsible for this dysregulation in the same DS subjects. Next, to prove its direct role in the pathogenesis of the syndrome, we will study the effect that modulation of mTOR activity and expression levels has on behavior impairments and neuropathology using in vivo models of DS. The results of our proposed studies will elucidate early changes and the functional consequences of altered proteostasis secondary to dysregulated mTOR in the development of the neuropathologic phenotype in individuals with DS. Importantly, our findings have the potential to identify new therapeutic opportunities for delaying its onset and /or halting its progression.


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 = $532,856 )
2025	2025	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Aging Research	001	3	8/11/2025	NON-COMPETING CONTINUATION	$43,498
2025	2025	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Aging Research	000	3	11/26/2024	NON-COMPETING CONTINUATION	$489,358
														Subtotal = $532,856

Issue Date FY: 2024 ( Subtotal = $529,653 )
2024	2024	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Aging Research	000	2	11/3/2023	NON-COMPETING CONTINUATION	$476,688
2024	2024	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Aging Research	001	2	4/30/2024	NON-COMPETING CONTINUATION	$52,965
														Subtotal = $529,653

Issue Date FY: 2023 ( Subtotal = $523,313 )
2023	2023	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Aging Research	000	1	11/30/2022	NEW	$523,313
														Subtotal = $523,313

Grand Total All Awards = $1,585,822

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Proteostasis dysregulation and the development of Alzheimer's-like neurodegeneration and dementia in Down syndrome

Award Number: R01AG080817

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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