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Alzheimer's Abeta, Tau, Apolipoproteins and Blood-brain barrier

Award Number: R01NS034467
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: 09/01/1995
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Alzheimer's Abeta, Tau, Apolipoproteins and Blood-brain barrier - ABSTRACT For the competing renewal of our R01NS34467-19 project, we propose to continue collaborative studies between the Zlokovic and the Holtzman labs aimed at understanding at the cellular, molecular and systems level, and in allele-specific and gender-specific manner apolipoprotein E (apoE) effects on the cerebrovascular system, specifically, 1) how they contribute to Alzheimer’s disease (AD) neurovascular dysfunction, neurodegenerative, amyloid-β (Aβ) and tau disorders; and 2) how targeting apoE-low density lipoprotein receptor-related protein 1 (LRP1) interactions on different cerebrovascular cell types can mitigate and/or block cerebrovascular and brain damage causing dementia in AD. We will focus on APOE4, the strongest genetic risk factor for AD, and APOE3 that carries a significantly lower risk for AD. Neurovascular apoE is produced by astrocytes, pericytes, and vascular smooth muscle cells (VSMCs). Based on published and our pilot data, we hypothesize that apoE isoform-specific interactions with LRP1 on brain vascular cells provide a pathogenic link to apoE-related cerebrovascular disorder by controlling in an apoE-isoform-specific manner: 1) cyclophilin A (CypA)-matrix- metalloproteinase 9 (MMP9) pathway which disrupts blood-brain barrier (BBB) and arterial blood vessels; and 2) Ab and tau clearance on capillary and arterial vessels. Specifically, the apoE4 pathophysiological cerebrovascular effects accelerate cerebrovascular, neurodegenerative, Ab and tau disorders, whereas apoE3 has less disruptive effects. ApoE allele-specific effects on BBB integrity, vascular and neuronal function and structure will be studied in new APOE knockinflox/flox E3F and E4F mice with apoE cell-specific deletion from astrocytes, pericytes, or VSMCs (AIM 1); and, in the context of Ab and tau pathology, in APP/PS1-21 mice (AIM 2) and P301S tau mice (AIM 3), respectively, crossed with our new E3F and E4F mice with apoE cell-specific deletion from astrocytes, pericytes, or VSMCs. We will therapeutically target LRP1 and CypA-MMP9 pathway with intravenous cell-specific adeno-associated virus (AAV)-mediated delivery of LRP1 minigene to endothelium and pericytes, and CypA inhibition with Debio 025. Understanding the effects of astrocyte-derived, pericyte- derived and/or VSMC-derived apoE on cerebrovascular and neuronal functions, Ab and tau clearance and pathology, in an allele-specific and gender-specific manner, will advance our understanding of the pathogenesis and treatment of AD neurovascular dysfunction, neurodegeneration, Ab and tau disorders. If successful, this could lead to new therapeutic approaches targeting LRP1 and/or CypA-MMP9 pathway in different brain vascular cells to mitigate and/or block apoE’s cerebrovascular and brain damage causing dementia in AD.


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 = $761,538 )
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	25	8/2/2024	NON-COMPETING CONTINUATION	$0
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	25	4/11/2024	NON-COMPETING CONTINUATION	$76,153
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	25	3/20/2024	NON-COMPETING CONTINUATION	$685,385
														Subtotal = $761,538

Issue Date FY: 2023 ( Subtotal = $772,703 )
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	24	2/3/2023	NON-COMPETING CONTINUATION	$772,703
														Subtotal = $772,703

Issue Date FY: 2022 ( Subtotal = $785,580 )
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	23	3/24/2022	NON-COMPETING CONTINUATION	$785,580
														Subtotal = $785,580

Issue Date FY: 2021 ( Subtotal = $799,216 )
2021	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	22	3/11/2021	NON-COMPETING CONTINUATION	$799,216
														Subtotal = $799,216

Issue Date FY: 2020 ( Subtotal = $828,100 )
2020	2020	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	21	9/26/2020	COMPETING CONTINUATION	$166,246
2020	2020	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	21	1/30/2020	COMPETING CONTINUATION	$828,100
2020	2018	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	20	9/26/2020	NON-COMPETING CONTINUATION	-$166,246
														Subtotal = $828,100

Issue Date FY: 2018 ( Subtotal = $599,100 )
2018	2018	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	20	4/25/2018	NON-COMPETING CONTINUATION	$59,910
2018	2018	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	20	3/15/2018	NON-COMPETING CONTINUATION	$539,190
														Subtotal = $599,100

Issue Date FY: 2017 ( Subtotal = $599,100 )
2017	2017	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	19	6/19/2017	NON-COMPETING CONTINUATION	$59,910
2017	2017	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	19	3/10/2017	NON-COMPETING CONTINUATION	$539,190
														Subtotal = $599,100

Issue Date FY: 2016 ( Subtotal = $599,100 )
2016	2016	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	18	3/14/2016	NON-COMPETING CONTINUATION	$599,100
														Subtotal = $599,100

Issue Date FY: 2015 ( Subtotal = $598,742 )
2015	2015	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	17	3/11/2015	NON-COMPETING CONTINUATION	$598,742
														Subtotal = $598,742

Issue Date FY: 2014 ( Subtotal = $613,400 )
2014	2014	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	16	1/14/2014	COMPETING CONTINUATION	-$613,400
2014	2014	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	16	1/24/2014	COMPETING CONTINUATION	$613,400
2014	2014	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	16	1/9/2014	COMPETING CONTINUATION	$613,400
														Subtotal = $613,400

Issue Date FY: 2004 ( Subtotal = $582,036 )
2004	2004	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14620	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	7/19/2004	NON-COMPETING CONTINUATION	$582,036
														Subtotal = $582,036

Issue Date FY: 2003 ( Subtotal = $566,802 )
2003	2003	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14620	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	7/10/2003	NON-COMPETING CONTINUATION	$566,802
														Subtotal = $566,802

Issue Date FY: 2002 ( Subtotal = $566,885 )
2002	2002	UNIVERSITY OF ROCHESTER	1325 MOUNT HOPE AVE, SUITE 260	ROCHESTER	NY	14620	MONROE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	7/29/2002	NON-COMPETING CONTINUATION	$566,885
														Subtotal = $566,885

Issue Date FY: 2001 ( Subtotal = $471,199 )
2001	2001	UNIVERSITY OF SOUTHERN CALIFORNIA	1014 CHILDS WAY	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	7/27/2001	COMPETING CONTINUATION	$471,199
														Subtotal = $471,199

Issue Date FY: 1998 ( Subtotal = $275,290 )
1998	1998	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Biological Basis Research in the Neurosciences	000	4	6/17/1998	NON-COMPETING CONTINUATION	$275,290
														Subtotal = $275,290

Grand Total All Awards = $9,418,791

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Alzheimer's Abeta, Tau, Apolipoproteins and Blood-brain barrier

Award Number: R01NS034467

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: 09/01/1995

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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