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Apolipoprotein E in Alzheimer's Disease: Molecular Mechanism

Award Number: R01AG048017
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2015
PERIOD OF PERFORMANCE END DATE: 03/31/2020

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Apolipoprotein E in Alzheimer's Disease: Molecular Mechanism - ¿ DESCRIPTION (provided by applicant): Apolipoprotein (apo) E4 increases the risk and lowers the age of onset for Alzheimer's disease (AD) in a gene dose-dependent manner. In most clinical studies, apoE4 carriers account for 60-75% of all AD cases, highlighting the importance of apoE4 in AD pathogenesis. Remarkably, the lifetime risk (LTR) estimate of developing AD by the age of 85 is ~60-70% for people with two copies of the apoE4 allele (~2% of the population) and ~30% for those with one copy of the apoE4 allele (~25% of the population), but is only ~10% in those with two copies of the apoE3 allele. Thus, apoE4 is considered a major gene, with semi-dominant inheritance, for AD. Although many hypotheses have been advanced, the exact mechanisms underlying the pathogenic actions of apoE4 remain unclear. This proposal builds on four novel findings from our studies of mouse models or human induced pluripotent stem cell (hiPSC)-derived neurons expressing different apoE isoforms. First, in apoE4-KI mice and mice expressing a neurotoxic apoE4 fragment, apoE4 and its fragment cause age- and tau-dependent impairment of GABAergic interneurons in the hilus of the hippocampus, and the extent of the impairment correlates with the extent of learning and memory deficits. Second, this apoE4-induced interneuron impairment also impairs adult hippocampal neurogenesis in mice. Third, the GABAA receptor potentiator pentobarbital rescues both the impaired neurogenesis and the deficits in learning and memory in apoE4-KI mice and apoE4 fragment transgenic mice. Fourth, apoE4 displays increased proteolysis and causes GABAergic interneuron death in hiPSC-derived neuronal cultures. These findings strongly suggest that apoE4 and its neurotoxic fragments cause hilar GABAergic interneuron impairment, contributing to learning and memory deficits and AD pathogenesis. The goal of this project is to determine how apoE4 impairs hilar GABAergic interneurons and how this process leads to spatial learning and memory deficits. Specifically, we will determine whether and how apoE4-induced impairments of GABAergic interneurons in the hilus of the dentate gyrus contribute to learning and memory deficits (Aim 1); explore the mechanisms by which apoE4 impairs hilar GABAergic interneurons (Aim 2); and determine whether and how apoE4 impairs human GABAergic interneurons derived from isogenic hiPSC lines with different apoE genotypes (Aim 3). These studies, involving in vitro, in vivo, and hiPSC approaches, will provide insights into the roles of apoE4 in both health and disease and may identify new therapeutic targets for apoE4-associated neurodegenerative disorders, particularly 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: 2021 ( Subtotal = $0 )
2021	2019	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Aging Research	000	5	11/2/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $388,065 )
2019	2019	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Aging Research	000	5	4/1/2019	NON-COMPETING CONTINUATION	$388,065
														Subtotal = $388,065

Issue Date FY: 2018 ( Subtotal = $388,065 )
2018	2018	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Aging Research	000	4	4/16/2018	NON-COMPETING CONTINUATION	$388,065
2018	2018	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Aging Research	001	4	6/26/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $388,065

Issue Date FY: 2017 ( Subtotal = $388,065 )
2017	2017	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Aging Research	001	3	6/22/2017	NON-COMPETING CONTINUATION	$38,807
2017	2017	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Aging Research	000	3	4/17/2017	NON-COMPETING CONTINUATION	$349,258
														Subtotal = $388,065

Issue Date FY: 2016 ( Subtotal = $388,065 )
2016	2016	J DAVID GLADSTONE INSTITUTES	P.O. BOX 419100	SAN FRANCISCO	CA	94141	SAN FRANCISCO	USA	Aging Research	000	2	4/6/2016	NON-COMPETING CONTINUATION	$388,065
														Subtotal = $388,065

Issue Date FY: 2015 ( Subtotal = $388,065 )
2015	2015	J DAVID GLADSTONE INSTITUTES	P.O. BOX 419100	SAN FRANCISCO	CA	94141	SAN FRANCISCO	USA	Aging Research	000	1	4/10/2015	NEW	$388,065
														Subtotal = $388,065

Grand Total All Awards = $1,940,325

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Apolipoprotein E in Alzheimer's Disease: Molecular Mechanism

Award Number: R01AG048017

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/15/2015

PERIOD OF PERFORMANCE END DATE: 03/31/2020

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