Wednesday, February 5, 2025 2/5/2025

Impairment of Ischemia-induced Vascular Functions by PS1 FAD Mutants

Award Number: R01NS047229
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Cerebral microvasculature abnormalities, such as degeneration of the capillary endothelium, are implicated in the genesis of Alzheimer's disease (AD) neuropathology. In addition, ischemic lesions that cause neuronal damage are often found in AD brains. The brain responds to ischemia by stimulating tissue neovascularization via sprouting angiogenesis; impairment of this function renders the brain vulnerable to the insult. It has been hypothesized that decreased angiogenesis in AD leads to insufficient blood flow and neuronal dysfunction in affected areas. The EphB4/ephrinB2 (efnB2) ligand-receptor system is known to regulate brain angiogenesis in response to ischemia. We present evidence that Presnilin1 (PS1), an important factor in familial AD (FAD), regulates angiogenic functions of EphB4/efnB2 such as stimulation of VE-cadherin angiogenic complexes in brain endothelial cells (ECs). We also found that this function is impaired by PS1 FAD mutants. In addition, we found that ischemia stimulates formation of the same angiogenic complexes in the brain and that this function is attenuated by PS1 FAD mutants together with ischemia-induced neovascularization and cerebral blood flow while neuronal death is increased. We also found that PS1 FAD mutants decrease the γ-secretase processing of efnB2 and production of the angiogenic peptide efnB2/CTF2 thus impairing the response of brain ECs to angiogenic factors. Together, our data support the hypothesis that PS1 FAD mutants inhibit ischemia-induced angiogenic functions of ECs by decreasing the γ-secretase processing of efnB2 and impairing the EphB4/efnB2 signaling, thus decreasing neovascularization in the adult brain and leading to increased vulnerability to this toxic insult and neuronal death. In this application we examine the roles of PS1 FAD mutants and γ-secretase on ischemia-induced angiogenic complexes, blood flow, angiogenesis and neuronal death. In addition, we propose to test a small peptide, which derives from the proteolytic processing of efnB2 by γ-secretase and which we found to rescue angiogenic functions of PS1 FAD ECs, for its pro-angiogenic and neuroprotective functions in brains expressing FAD mutants. In addition we aim to search for novel ischemia-induced angiogenic pathways that are impaired by PS1 FAD mutants and examine whether VE-cadherin angiogenic complexes and angiogenic protein expression are impaired in brains of human PS1 FAD and AD patients.


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 = $515,529 )
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	19	1/1/2025	NON-COMPETING CONTINUATION	$515,529
														Subtotal = $515,529

Issue Date FY: 2024 ( Subtotal = $684,839 )
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	18	5/1/2024	NON-COMPETING CONTINUATION	$20,545
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	18	4/10/2024	NON-COMPETING CONTINUATION	$47,938
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	18	12/29/2023	NON-COMPETING CONTINUATION	$616,356
														Subtotal = $684,839

Issue Date FY: 2023 ( Subtotal = $646,658 )
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	17	12/16/2022	NON-COMPETING CONTINUATION	$581,992
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	17	1/30/2023	NON-COMPETING CONTINUATION	$64,666
														Subtotal = $646,658

Issue Date FY: 2022 ( Subtotal = $605,083 )
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	16	5/13/2022	NON-COMPETING CONTINUATION	$60,509
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	16	12/31/2021	NON-COMPETING CONTINUATION	$544,574
														Subtotal = $605,083

Issue Date FY: 2021 ( Subtotal = $606,710 )
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	1/14/2021	COMPETING CONTINUATION	$606,710
2021	2019	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	14	1/21/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $606,710

Issue Date FY: 2019 ( Subtotal = $370,781 )
2019	2019	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	11/22/2018	NON-COMPETING CONTINUATION	$370,781
														Subtotal = $370,781

Issue Date FY: 2018 ( Subtotal = $370,781 )
2018	2018	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	13	4/26/2018	NON-COMPETING CONTINUATION	$37,079
2018	2018	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	11/21/2017	NON-COMPETING CONTINUATION	$333,702
														Subtotal = $370,781

Issue Date FY: 2017 ( Subtotal = $370,781 )
2017	2017	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	12/8/2016	NON-COMPETING CONTINUATION	$333,702
2017	2017	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	12	6/6/2017	NON-COMPETING CONTINUATION	$37,079
														Subtotal = $370,781

Issue Date FY: 2016 ( Subtotal = $370,781 )
2016	2016	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	11/6/2015	NON-COMPETING CONTINUATION	$333,702
2016	2016	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	11	3/24/2016	NON-COMPETING CONTINUATION	$37,079
														Subtotal = $370,781

Issue Date FY: 2015 ( Subtotal = $370,173 )
2015	2015	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	10	2/1/2015	COMPETING CONTINUATION	$0
2015	2015	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	1/26/2015	COMPETING CONTINUATION	$370,173
2015	2013	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	9	1/28/2015	NON-COMPETING CONTINUATION	$0
														Subtotal = $370,173

Issue Date FY: 2013 ( Subtotal = $350,648 )
2013	2013	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	6/3/2013	NON-COMPETING CONTINUATION	$350,648
														Subtotal = $350,648

Issue Date FY: 2012 ( Subtotal = $363,366 )
2012	2012	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	5/28/2012	NON-COMPETING CONTINUATION	$363,366
														Subtotal = $363,366

Issue Date FY: 2011 ( Subtotal = $363,366 )
2011	2011	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	6/2/2011	NON-COMPETING CONTINUATION	$363,366
														Subtotal = $363,366

Issue Date FY: 2010 ( Subtotal = $367,074 )
2010	2010	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK	NY	10029	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	5/18/2010	NON-COMPETING CONTINUATION	$367,074
														Subtotal = $367,074

Issue Date FY: 2009 ( Subtotal = $370,781 )
2009	2009	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK	NY	10029	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	6/24/2009	COMPETING CONTINUATION	$370,781
														Subtotal = $370,781

Issue Date FY: 2007 ( Subtotal = $371,658 )
2007	2007	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	2/5/2007	NON-COMPETING CONTINUATION	$371,658
														Subtotal = $371,658

Issue Date FY: 2006 ( Subtotal = $382,758 )
2006	2006	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/25/2006	NON-COMPETING CONTINUATION	$382,758
														Subtotal = $382,758

Issue Date FY: 2005 ( Subtotal = $391,969 )
2005	2005	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/10/2004	NON-COMPETING CONTINUATION	$391,969
														Subtotal = $391,969

Issue Date FY: 2004 ( Subtotal = $390,040 )
2004	2004	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/17/2003	NEW	$390,040
														Subtotal = $390,040

Grand Total All Awards = $8,263,776

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Impairment of Ischemia-induced Vascular Functions by PS1 FAD Mutants

Award Number: R01NS047229

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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