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Cell and Molecular Pathobiology of Alzheimer's Disease

Award Number: P01AG017617
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2000
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Cell and Molecular Pathobiology of Alzheimer's Disease - ABSTRACT Our PPG renewal application addresses the cell and molecular basis of late-onset Alzheimer’s disease (AD) and explores innovative approaches toward its prevention and therapy. Our main focus is the neuronal “Lysosomal Network” (LN), encompassing the endosomal-lysosomal (EL) pathway and autophagy, which is strongly believed to play a central role in AD pathogenesis based on mounting genetic and biochemical evidence. Our PPG was first to show LN dysfunction as being pivotal to AD development, arising at the earliest stage of disease, progressing to involve multiple EL and autophagy sites, and strongly dependent on the amyloid-β precursor protein (APP) gene but not Aβ. During this term, we established that LN dysfunction critically involves the direct interaction of the β-site cleaved carboxyl-terminal fragment (βCTF) of APP with a rab5 protein complex on endosomes resulting in the pathological rab5 activation known to initiate endosome dysfunction and cause cholinergic neurodegeneration. Additionally, we showed that acidification of lysosomes requires presenilin1 (PS1) and familial AD mutations of PS1 drive LN dysfunction that promotes neuritic dystrophy, amyloidogenesis, and neurodegeneration. These findings and new PPG data support our view that AD development is multifactorial, involving diverse pathological actions on the LN by AD risk genes, including ApoE4. We now propose to test the hypothesis that key genetic and environmental risk factors for late-onset AD operate via molecular mechanisms similar to those in early-onset AD and are potentially modifiable for significant therapeutic gain. The Program consists of 3 cores and 4 highly inter-dependent projects, which comprehensively investigate all major components of the LN to define multiple mechanisms underlying LN dysfunction in AD. Project 1 (Mathews) defines mechanisms and modifiers of early endosomal trafficking and signaling mediated by ApoE4, CTF and cholesterol. Project 2 (Nixon, Cuervo) addresses βCTF dysregulation of lysosomal function, including chaperone-mediated autophagy (CMA), with a mechanistic focus on defective lysosomal acidification as a key disease driver and innovative therapeutic target. Project 3 (Levy) clarifies the multi-faceted impact of LN dysfunction on the release of extracellular vesicles from multiple LN organelles in neurons or glia and the potential for therapeutic modulation. Project 4 (Ginsberg, Nixon) examines in vivo LN function in homogeneous neuronal populations as influenced by βCTF, rab5, and ApoE4 and the role of calorie restriction (CR) and CR mimetics as therapeutic modifiers of LN dysfunction via an hypothesized enhancement of autophagy flux. Tight programmatic integration is enhanced by innovative cell-population- specific transcriptomic and bioinformatic approaches, neuron- and glial specific autophagy reporter mice, and novel transgenic and KO mice enabling for the first time evaluations of rab5 and CMA in vivo in relation to AD and aging. The Program is expected to yield new insights relevant to late-onset AD and its treatment.


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 = -$1,673,090 )
2025	2021	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD BLDG 35	ORANGEBURG	NY	10962	ROCKLAND	USA	Aging Research	000	20	7/29/2025	NON-COMPETING CONTINUATION	-$1,673,090
														Subtotal = -$1,673,090

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD BLDG 35	ORANGEBURG	NY	10962	ROCKLAND	USA	Aging Research	000	20	3/26/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Aging Research	000	20	3/7/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $2,424,969 )
2021	2021	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Aging Research	002	20	3/19/2021	NON-COMPETING CONTINUATION	$2,424,969
2021	2015	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Aging Research	001	15	10/3/2020	NON-COMPETING CONTINUATION	$336
2021	2015	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Aging Research	000	15	10/1/2020	NON-COMPETING CONTINUATION	-$336
														Subtotal = $2,424,969

Issue Date FY: 2020 ( Subtotal = $2,676,872 )
2020	2020	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Aging Research	001	19	9/9/2020	SUPPLEMENT FOR EXPANSION	$249,884
2020	2020	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Aging Research	000	19	3/12/2020	NON-COMPETING CONTINUATION	$2,426,988
														Subtotal = $2,676,872

Issue Date FY: 2019 ( Subtotal = $2,430,420 )
2019	2019	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Aging Research	000	18	4/19/2019	NON-COMPETING CONTINUATION	$2,430,420
														Subtotal = $2,430,420

Issue Date FY: 2018 ( Subtotal = $2,430,420 )
2018	2018	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Aging Research	006	17	4/26/2018	NON-COMPETING CONTINUATION	$2,430,420
2018	2017	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Aging Research	000	16	3/27/2018	COMPETING CONTINUATION	-$2,443,714
2018	2017	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Aging Research	005	16	4/9/2018	COMPETING CONTINUATION	$4,230
2018	2017	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Aging Research	001	16	3/29/2018	COMPETING CONTINUATION	$2,443,714
2018	2016	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Aging Research	004	15	4/9/2018	SUPPLEMENT FOR EXPANSION	-$4,230
2018	2016	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Aging Research	003	15	4/6/2018	SUPPLEMENT FOR EXPANSION	$2,356
2018	2015	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Aging Research	002	15	4/6/2018	NON-COMPETING CONTINUATION	-$2,356
														Subtotal = $2,430,420

Issue Date FY: 2017 ( Subtotal = $2,443,714 )
2017	2017	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Aging Research	002	16	5/30/2017	COMPETING CONTINUATION	$437,090
2017	2017	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Aging Research	001	16	3/30/2017	COMPETING CONTINUATION	$2,006,624
2017	2015	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Aging Research	000	15	3/30/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,443,714

Issue Date FY: 2016 ( Subtotal = $674,732 )
2016	2016	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC	150 BROADWAY SUITE 301	MENANDS	NY	12204	ALBANY	USA	Aging Research	000	15	7/14/2016	SUPPLEMENT FOR EXPANSION	$674,732
														Subtotal = $674,732

Issue Date FY: 2015 ( Subtotal = $1,916,714 )
2015	2015	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC	150 BROADWAY SUITE 301	MENANDS	NY	12204	ALBANY	USA	Aging Research	000	15	6/9/2015	NON-COMPETING CONTINUATION	$1,916,714
														Subtotal = $1,916,714

Issue Date FY: 2014 ( Subtotal = $1,975,994 )
2014	2014	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC	150 BROADWAY SUITE 301	MENANDS	NY	12204	ALBANY	USA	Aging Research	000	14	5/20/2014	NON-COMPETING CONTINUATION	$1,975,994
														Subtotal = $1,975,994

Issue Date FY: 2013 ( Subtotal = $1,867,316 )
2013	2013	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC	150 BROADWAY SUITE 301	MENANDS	NY	12204	ALBANY	USA	Aging Research	000	13	8/21/2013	NON-COMPETING CONTINUATION	$1,867,316
														Subtotal = $1,867,316

Issue Date FY: 2012 ( Subtotal = $1,975,994 )
2012	2012	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC	150 BROADWAY SUITE 301	MENANDS	NY	12204	ALBANY	USA	Aging Research	000	12	8/21/2012	NON-COMPETING CONTINUATION	$1,975,994
														Subtotal = $1,975,994

Issue Date FY: 2011 ( Subtotal = $2,430,905 )
2011	2011	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC	150 BROADWAY SUITE 301	MENANDS	NY	12204	ALBANY	USA	Aging Research	004	11	9/22/2011	COMPETING CONTINUATION	$1,995,905
2011	2011	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC	150 BROADWAY SUITE 301	MENANDS	NY	12204	ALBANY	USA	Aging Research	002	10	6/20/2011	SUPPLEMENT FOR EXPANSION	$435,000
2011	2009	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC	150 BROADWAY SUITE 301	MENANDS	NY	12204	ALBANY	USA	Aging Research	001	10	4/6/2011	SUPPLEMENT FOR EXPANSION	$0
2011	2009	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC	150 BROADWAY SUITE 301	MENANDS	NY	12204	ALBANY	USA	Aging Research	000	10	4/6/2011	NON-COMPETING CONTINUATION	$0
2011	2009	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC	150 BROADWAY SUITE 301	MENANDS	NY	12204	ALBANY	USA	Aging Research	003	10	9/22/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,430,905

Issue Date FY: 2009 ( Subtotal = $2,141,838 )
2009	2009	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC	150 BROADWAY SUITE 301	MENANDS	NY	12204	ALBANY	USA	Aging Research	000	10	6/8/2009	NON-COMPETING CONTINUATION	$1,983,838
2009	2009	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC	150 BROADWAY SUITE 301	MENANDS	NY	12204	ALBANY	USA	Aging Research	001	10	6/9/2009	SUPPLEMENT FOR EXPANSION	$158,000
														Subtotal = $2,141,838

Issue Date FY: 2008 ( Subtotal = $1,930,953 )
2008	2008	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC	150 BROADWAY SUITE 301	MENANDS	NY	12204	ALBANY	USA	Aging Research	000	9	5/6/2008	NON-COMPETING CONTINUATION	$1,930,953
														Subtotal = $1,930,953

Issue Date FY: 2007 ( Subtotal = $1,924,962 )
2007	2007	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC	150 BROADWAY SUITE 301	MENANDS	NY	12204	ALBANY	USA	Aging Research	000	8	6/7/2007	NON-COMPETING CONTINUATION	$1,924,962
														Subtotal = $1,924,962

Grand Total All Awards = $38,337,261

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Cell and Molecular Pathobiology of Alzheimer's Disease

Award Number: P01AG017617

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/15/2000

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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