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Charting vascular contributions to white matter disease in familial Alzheimer's disease and CADASIL

Award Number: RF1NS110048
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2018
PERIOD OF PERFORMANCE END DATE: 05/31/2023

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Charting vascular contributions to white matter disease in familial Alzheimer's disease and CADASIL - Mutations in NOTCH3 cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leu- koencephalopathy (CADASIL), a neurological condition characterized by small vessel disease and white mat- ter degeneration. Mutations in Presenilin 1 (PSEN1) are the most prevalent cause of early onset familial Alz- heimer’s disease (AD). Though CADASIL and PSEN1-associated AD are considered pure disease models, there is evidence of potential mechanistic overlap because PSEN1 function is required for the activation of Notch receptors including Notch3. Supporting this view, clinical studies showed substantial white matter dis- ease in PSEN1 mutation carriers and cerebral spinal fluid analyses of CADASIL patients show changes indica- tive of abnormal amyloid metabolism. We hypothesize that SVD and its associated white matter disease occurs due to dysregulation of homeostatic PSEN1/NOTCH3 pathways that preserve vessel and white matter integrity in adults under physiological conditions and are dysfunctional in familial forms of de- mentia. To test this hypothesis, we propose to leverage our animal models with Notch3 and Psen1 mutations. We will also conduct parallel studies in postmortem human tissue from PSEN1 and NOTCH3 mutation carriers to identify common pathobiological mechanisms. We propose two research aims: Aim 1: To examine functional links between PSEN1/NOTCH3 signaling and vascular degeneration us- ing mouse models and postmortem human tissue. We will use Notch3 and Psen1 mutant mouse models and postmortem human tissue from CADASIL and AD patients to examine the role of the PSEN1/NOTCH3 pathway on SVD. We will conduct studies in mice carrying single mutations and in mice carrying a CADASIL mutation in Notch3 and an AD-causing PSEN1 mutation. Aim 2: To investigate functional links between PSEN1/NOTCH3 signaling and brain white matter dis- ease. We will use Notch3 and PSEN1 mutant mouse models and postmortem human tissue to examine the role of the PSEN1/NOTCH3 pathway on white matter degeneration. We will conduct analyses in mice express- ing CADASIL mutations in mural cells and also in mice expressing mutant Notch3 in oligodendrocytes, another site of Notch3 expression that has been implicated in CADASIL pathobiology. These experiments will tell us the extent to which PSEN1/NOTCH3 dysfunction impact signaling in molecular pathways implicated in SVD and white matter degeneration potentially leading to the identification of novel therapeutic approaches.


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: 2024 ( Subtotal = $0 )
2024	2019	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/26/2024	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2018	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/8/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	9/1/2020	SUPPLEMENT FOR EXPANSION	$0
2020	2018	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/31/2020	NEW	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $49,896 )
2019	2019	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	8/30/2019	SUPPLEMENT FOR EXPANSION	$49,896
2019	2018	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/6/2019	NEW	$0
														Subtotal = $49,896

Issue Date FY: 2018 ( Subtotal = $3,524,983 )
2018	2018	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/19/2018	NEW	$3,524,983
														Subtotal = $3,524,983

Grand Total All Awards = $3,574,879

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Charting vascular contributions to white matter disease in familial Alzheimer's disease and CADASIL

Award Number: RF1NS110048

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2018

PERIOD OF PERFORMANCE END DATE: 05/31/2023

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