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Investigating the vulnerability of WFS1-expressing excitatory neurons to tau pathology in early Alzheimer's disease.

Award Number: K01AG056673
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 11/01/2018
PERIOD OF PERFORMANCE END DATE: 03/31/2022

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Investigating the vulnerability of WFS1-expressing excitatory neurons to tau pathology in early Alzheimer's disease. - Project Summary/Abstract In the earliest stages of Alzheimer’s disease (AD), hyperphosphorylated and conformationally abnormal (pathological) tau in the form of tangles, and selective neuronal loss have been found in the superficial layers of the entorhinal cortex and in the CA1 of hippocampus. However, the precise neuronal cell types that accumulate tangles and the biochemical pathways mediating this selective neuronal vulnerability are not known. We, and others, have found that excitatory neurons in the EC and CA1 of hippocampus are particularly vulnerable to tau pathology. Notably, Wolfram Syndrome 1 (WFS1), a transmembrane glycoprotein localized to the endoplasmic reticulum (ER), is differentially expressed in excitatory neurons in those two regions. WFS1 dysfunction has been found to contribute to neurodegeneration as well as stress and depression, possibly by regulating the endoplasmic reticulum (ER) stress and/or the hypothalamic–pituitary–adrenal (HPA) axis. Based on these observations, I hypothesize that tau pathology will reduce the expression of WFS1, resulting in ER and cytosolic calcium dyshomeostasis, persistent activation of ER stress pathways and other as yet unknown pathways, which in turn will exacerbate tau pathology, synaptic dysfunction, neuronal loss and cognitive deficits. To test this hypothesis, this proposal will (1) determine if WFS1-expressing excitatory neurons in the superficial layers of medial entorhinal cortex (MEC) and in the CA1 of hippocampus are vulnerable to tau pathology in tau transgenic mice and in human AD; (2) investigate whether overexpression of WFS1 ameliorates ER calcium dyshomeostasis, ER stress, tau pathology, glial activation, synaptic dysfunction and cognitive deficits in rTg4510 tau mice; (3) explore whether conditional knockout of WFS1 in the brain exacerbates ER calcium dyshomeostasis, ER stress, tau pathology, glial activation, synaptic dysfunction and cognitive deficits in rTg4510 tau mice; and (4) define the interaction between WFS1 and tau, and biochemical pathways in addition to the ER stress pathways that underlie the vulnerability of WFS1-expressing excitatory neurons to tau pathology in tau transgenic mice and in human AD. Identifying the molecular mechanisms underlying pathological tau- mediated neuronal vulnerability and neurodegeneration in AD could aid in the discovery of novel drug targets that can be targeted to protect vulnerable neurons. In addition, the approaches proposed to characterize cell populations vulnerable to pathological proteins in AD can be applied to a wide range of degenerative diseases that also show selective, cellular vulnerability.


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: 2022 ( Subtotal = -$301 )
2022	2021	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Aging Research	000	5	8/19/2022	NON-COMPETING CONTINUATION	-$301
														Subtotal = -$301

Issue Date FY: 2021 ( Subtotal = $124,308 )
2021	2021	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Aging Research	000	5	4/1/2021	NON-COMPETING CONTINUATION	$124,308
														Subtotal = $124,308

Issue Date FY: 2020 ( Subtotal = $124,308 )
2020	2020	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Aging Research	000	4	3/27/2020	NON-COMPETING CONTINUATION	$124,308
														Subtotal = $124,308

Issue Date FY: 2019 ( Subtotal = $124,308 )
2019	2019	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Aging Research	004	3	5/13/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$128,022
2019	2019	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Aging Research	001	3	3/7/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$124,308
2019	2018	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	003	2	5/13/2019	NON-COMPETING CONTINUATION	-$126,009
2019	2018	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	000	2	3/4/2019	NON-COMPETING CONTINUATION	$0
2019	2017	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	002	1	5/13/2019	NEW	-$2,013
														Subtotal = $124,308

Issue Date FY: 2018 ( Subtotal = $126,009 )
2018	2018	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	000	2	4/16/2018	NON-COMPETING CONTINUATION	$126,009
														Subtotal = $126,009

Issue Date FY: 2017 ( Subtotal = $126,009 )
2017	2017	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	000	1	7/13/2017	NEW	$126,009
														Subtotal = $126,009

Grand Total All Awards = $624,641

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Investigating the vulnerability of WFS1-expressing excitatory neurons to tau pathology in early Alzheimer's disease.

Award Number: K01AG056673

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 11/01/2018

PERIOD OF PERFORMANCE END DATE: 03/31/2022

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