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Mechanisms transducing insulin and insulin resistance in the hippocampus

Award Number: R01AG050598
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2016
PERIOD OF PERFORMANCE END DATE: 01/31/2023

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Mechanisms transducing insulin and insulin resistance in the hippocampus - DESCRIPTION (provided by applicant): The goal of this proposal is to prevent and treat the cognitive and neural impairment associated with impaired brain insulin signaling. Such signaling is now recognized as central to the impact of both type 2 diabetes (T2DM) and Alzheimer's disease (AD), which is now commonly characterized as 'type 3 diabetes' [1, 2]. Work in our lab, funded by the grant of which this is a renewal, showed that insulin is a key component of hippocampal metabolism and memory processes and that systemic insulin resistance impairs both hippocampal metabolism and cognitive function [3-6]. However, little is known about the molecular mechanism(s) by which insulin regulates cognitive and neural processes. Similarly, the clinical fact that T2DM causes cognitive impairment is well-established, but not understood at a cellular or molecular level. Several clinical studies have shown a clear link between T2DM and development of AD [7-16]; conversely, AD patients show reduced hippocampal insulin signaling that accompanies hypometabolism and abnormal accumulation of beta-amyloid (Aβ). Several in vitro studies suggested that insulin and Aβ oppose each other at a molecular level [17-24]; recent in vivo work from our lab showed that administration of oligomeric Aβ to the hippocampus caused rapid cognitive impairment, reduced glucose metabolism, and impaired translocation of the insulin-regulated glucose transporter GluT4 [6]: this closely resembles hippocampal insulin resistance. Further, our animal model of diet-induced T2DM causes elevation of hippocampal amyloid [25]: a key hypothesis presented here is that this causes T2DM-associated cognitive impairment as well as the elevated risk of dementia. Understanding insulin's modulation of hippocampal processes, and how this modulation is impaired by insulin resistance and/or Aβ, is central to developing treatment for T2DM and/or AD. Long-term, the public health goal of this work is to identify therapeutic targets for prevention and treatment of brain dysfunction in T2DM and AD. The experiments proposed here build on the successful progress during this grant's first funding period. We will determine the molecular effectors by which insulin, and conversely insulin-resistance, impact hippocampal function. As part of this, we will directly manipulate candidate effectors, supported by preliminary data, including GluT4 and multiple forms of Aβ. The second aim, again emerging from strong preliminary data, is to investigate the different involvement of insulin and downstream effectors in distinct stages of hippocampal memory processing.


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 = -$40,538 )
2024	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Aging Research	000	5	11/22/2023	NON-COMPETING CONTINUATION	-$40,538
														Subtotal = -$40,538

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Aging Research	000	5	1/12/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $379,742 )
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Aging Research	000	5	1/30/2020	NON-COMPETING CONTINUATION	$379,742
														Subtotal = $379,742

Issue Date FY: 2019 ( Subtotal = $379,882 )
2019	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Aging Research	000	4	1/28/2019	NON-COMPETING CONTINUATION	$379,882
														Subtotal = $379,882

Issue Date FY: 2018 ( Subtotal = $380,018 )
2018	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Aging Research	001	3	4/25/2018	NON-COMPETING CONTINUATION	$38,003
2018	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Aging Research	002	3	5/2/2018	NON-COMPETING CONTINUATION	$0
2018	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Aging Research	000	3	1/19/2018	NON-COMPETING CONTINUATION	$342,015
														Subtotal = $380,018

Issue Date FY: 2017 ( Subtotal = $379,909 )
2017	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Aging Research	001	2	6/14/2017	NON-COMPETING CONTINUATION	$37,992
2017	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Aging Research	000	2	1/26/2017	NON-COMPETING CONTINUATION	$341,917
														Subtotal = $379,909

Issue Date FY: 2016 ( Subtotal = $392,817 )
2016	2016	RESEARCH FOUNDATION OF STATE UNIV OF NEW YORK (SUNY)	P.O. BOX 9	ALBANY	NY	12201	ALBANY	USA	Aging Research	000	1	4/28/2016	NEW	$392,817
														Subtotal = $392,817

Grand Total All Awards = $1,871,830

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Mechanisms transducing insulin and insulin resistance in the hippocampus

Award Number: R01AG050598

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2016

PERIOD OF PERFORMANCE END DATE: 01/31/2023

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