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Mechanisms of APP and APLP2 function at synapses

Award Number: R01AG052286
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2016
PERIOD OF PERFORMANCE END DATE: 12/31/2020

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Mechanisms of APP and APLP2 function at synapses - DESCRIPTION (provided by applicant): Alzheimer's Disease (AD) is the most common cause of ageing-dependent dementia in the world and is associated with cerebral amyloid plaques, mostly composed of Aβ peptides. These peptides are produced by a double cleavage of the amyloid precursor protein (APP). BACE1 cleavage produces the C-terminal fragment, β-CTF, which is then processed into several Aβ isoforms by γ-secretase. Genetic data suggest that regulation of APP processing contributes to AD. In addition, a polymorphism of APP that reduces processing of APP by BACE1 protects from sporadic AD and from normal aging-dependent cognitive decline. Thus, the human genetic evidence indicates that APP and APP processing are important for normal cognitive functions. To gain insights into the function of APP in the central nervous system, we have characterized the brain interactome of the APP intracellular domain. We isolated several proteins including proteins that regulate synaptic vesicles exocytosis (which we collectively refer to as the APP presynaptic interactome or Appresyome) and a multimolecular complex composing the E3 ligase CRL4CRBN. Interestingly, one of the components of CRL4CRBN, i.e. CRBN, is coded by a gene linked to intellectual disability. Our preliminary studies suggest that APP regulates the probability of release of glutamatergic synaptic vesicles and that this function is regulated by APP processing by BACE1. We also found that CRL4CRBN mediates ubiquitination of Snap25, Vamp2 and Stxbp1, three proteins that regulate synaptic vesicles exocytosis and that are also part of the Appresyome. Of note, CRL4CRBN and the Appresyome bind two distinct regions of the APP intracellular domain. Finally, we found that APLP2, a member of the APP protein family, shares many of these APP functions. In this study we will analyze the role of APP and APLP2 in synaptic transmission as well as the molecular mechanisms underlying it. We will also study how processing of APP (and APLP2) regulates synaptic transmission. Lastly, we will analyze the function of CRL4CRBN and of the CRL4CRBN/APP-CRL4CRBN/APLP2 complexes. Our studies will contribute to our understanding of the synaptic function of APP, BACE1 and CRBN and, perhaps, uncover signaling pathways that may be altered in AD. Thus, this study may shed light on the pathogenesis of AD, as well as unveil novel targets for disease-modifying AD drugs.


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: 2021 ( Subtotal = $0 )
2021	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	000	5	4/21/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $686,386 )
2020	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	000	5	1/24/2020	NON-COMPETING CONTINUATION	$686,386
														Subtotal = $686,386

Issue Date FY: 2019 ( Subtotal = $686,386 )
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	000	4	12/24/2018	NON-COMPETING CONTINUATION	$686,386
														Subtotal = $686,386

Issue Date FY: 2018 ( Subtotal = $701,136 )
2018	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	003	3	2/14/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$427,689
2018	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	005	3	5/2/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2018	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	004	3	4/25/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$68,638
2018	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	001	3	1/19/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$632,498
2018	2017	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	002	2	2/14/2018	NON-COMPETING CONTINUATION	-$427,689
2018	2017	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	000	2	1/17/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $701,136

Issue Date FY: 2017 ( Subtotal = $718,359 )
2017	2017	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	000	2	12/23/2016	NON-COMPETING CONTINUATION	$646,523
2017	2017	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	001	2	6/21/2017	NON-COMPETING CONTINUATION	$71,836
														Subtotal = $718,359

Issue Date FY: 2016 ( Subtotal = $735,109 )
2016	2016	ALBERT EINSTEIN COLLEGE OF MEDICINE INC	111 E 210TH ST	BRONX	NY	10467	BRONX	USA	Aging Research	000	1	1/18/2016	NEW	$605,804
2016	2016	ALBERT EINSTEIN COLLEGE OF MEDICINE INC	111 E 210TH ST	BRONX	NY	10467	BRONX	USA	Aging Research	001	1	3/10/2016	NEW	$129,305
														Subtotal = $735,109

Grand Total All Awards = $3,527,376

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Mechanisms of APP and APLP2 function at synapses

Award Number: R01AG052286

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2016

PERIOD OF PERFORMANCE END DATE: 12/31/2020

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