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Identify common mechanisms of neurodegeneration between Alzheimer's disease and Down syndrome

Award Number: R01AG059627
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2018
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Identify common mechanisms of neurodegeneration between Alzheimer's disease and Down syndrome - Growing evidence indicates that Alzheimer's disease (AD) starts decades before its clinical manifestation and that early clinical interventions are needed to effectively mitigate the progression of AD. However, the initial triggers in the cascade of pathological events leading to AD remain elusive. Virtually 100% of people with Down syndrome (DS) will show brain accumulation of amyloid-β (Aβ) and tau in their fifth decade of life. Despite these striking data, little is known about the processes linking DS to AD. We postulate that dissecting the molecular mechanisms driving AD pathology in DS patients will lead to a better understanding of the etiology of AD. Published work and our preliminary data indicate that the mammalian target of rapamycin (mTOR) is hyperactive in human and animal models of DS and AD. Further, we and others have shown that hyperactive mTOR signaling facilitates the accumulation of Aβ and tau. Together, these novel and exciting findings may answer a fundamental unresolved question: which event triggers the development of AD neuropathology in DS. The answer to this question will unveil mechanistic changes linked to the etiology of AD. The overall hypothesis of this application is that Dysfunctional TSC2 complex increases mTOR activity in DS, which in turn contributes to the development of AD-like neurodegeneration by inducing necroptosis. To this end, we propose three Aims. Aim 1 will test the hypothesis that dysfunctional TSC2 activity contributes to mTOR hyperactivity in DS. Specifically, we will use three complementary approaches to systematically dissect the molecular pathways leading to dysfunctional TSC2/mTOR axis in DS. These experiments will elucidate the signaling pathways leading to mTOR hyperactivity in DS, which is a critical step towards understanding the link between DS and AD. Specific Aim 2 will test the hypothesis that hyperactive mTOR signaling contributes to the development of AD pathology in DS. Specifically, we will use three complementary approaches: (1) we will test the effects of reducing neuronal mTOR activity on the development of AD-like phenotype in Ts65Dn mice; (2) we will determine whether further increasing neuronal mTOR signaling in Ts65Dn mice, prior to the increase in Aβ levels, exacerbates AD-like pathology and cognitive deficits; (3) we will use state-of-the-art isobaric tags for relative and absolute quantitation (iTRAQ) technology to identify proteins that are differentially regulated by mTOR hyperactivity in DS. These experiments will lead to a better understanding of the mechanistic relationship among DS, mTOR, and AD. Specific Aim 3 will test whether hyperactive mTOR contributes to neuronal death by activating necroptosis. The mechanisms that govern neuronal death in DS and AD remain poorly understood. Our preliminary data show that necroptosis, a programmed form of necrosis, contributes to neurodegeneration in AD and DS mouse models. We will use complementary experiments to modulate necroptotic signaling and mTOR activity in animals and primary neurons. These experiments will lead to a better understanding of the mechanism leading to cell loss in DS and AD and will identify new therapeutic targets for these two disorders.


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	2022	ARIZONA STATE UNIVERSITY	1475 N SCOTTSDALE RD STE 200	SCOTTSDALE	AZ	85257	MARICOPA	USA	Aging Research	000	5	12/1/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	000	5	5/24/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $516,078 )
2022	2022	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	000	5	5/13/2022	NON-COMPETING CONTINUATION	$516,078
														Subtotal = $516,078

Issue Date FY: 2021 ( Subtotal = $575,901 )
2021	2021	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	000	4	6/30/2021	NON-COMPETING CONTINUATION	$575,901
														Subtotal = $575,901

Issue Date FY: 2020 ( Subtotal = $687,475 )
2020	2020	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	000	3	6/17/2020	NON-COMPETING CONTINUATION	$687,475
														Subtotal = $687,475

Issue Date FY: 2019 ( Subtotal = $790,279 )
2019	2019	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	000	2	7/18/2019	NON-COMPETING CONTINUATION	$790,279
														Subtotal = $790,279

Issue Date FY: 2018 ( Subtotal = $542,974 )
2018	2018	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	000	1	9/11/2018	NEW	$542,974
														Subtotal = $542,974

Grand Total All Awards = $3,112,707

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Identify common mechanisms of neurodegeneration between Alzheimer's disease and Down syndrome

Award Number: R01AG059627

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2018

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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