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Investigating tau and ApoE4-mediated alterations in oligodendrocyte progenitor cells

Award Number: R01AG071513
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2022
PERIOD OF PERFORMANCE END DATE: 05/18/2025

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Investigating tau and ApoE4-mediated alterations in oligodendrocyte progenitor cells - PROJECT SUMMARY/ABSTRACT As the most common cause of dementia, Alzheimer’s disease (AD) is pathologically defined by amyloid beta (Aβ) deposition in senile plaques and tau aggregation in neurofibrillary tangles (NFTs). In addition to amyloidosis and tauopathy, demyelination is also a consistent, yet often overlooked, feature of AD. Notably, myelin loss is detected even at early stages of disease with decreases observed in patients with mild cognitive impairment (MCI). This implicates that dysregulation of the oligodendrocyte cell population, the brain’s myelin- producing cells, may be a critical factor in AD pathophysiology. Several recent studies from multiple groups consistently identified transcriptional alterations in myelination networks as a key feature of AD, underscoring the great need to elucidate disease-related alterations in the oligodendrocyte population to provide novel insights into AD pathophysiology. Of particular relevance, tau accumulation is associated with loss of white matter integrity in both human patients and mouse models of tauopathy. White matter abnormalities have even been detected in cognitively-normal carriers of the apolipoprotein E ε4 (APOE ε4) genotype, a population at high risk of developing AD. Given that ApoE4 has been shown to potentiate tau toxicity and ischemia-induced white matter damage in mice, these findings may indicate that tau burden and ApoE4 converge to drive white matter abnormalities in AD. Considering that oligodendrocyte progenitor cells (OPCs) respond to white matter damage by migrating to the site of injury and differentiating into myelinating oligodendrocytes to repair the lesion, a key question is why OPCs and/or oligodendrocytes fail to correct white matter abnormalities in the presence of abnormal forms of tau and/or ApoE4. A recent study found that OPCs in both postmortem brain and a mouse model of AD exhibited markers of cellular senescence, with pharmacologic removal of senescent OPCs alleviating inflammation and cognitive defects in mice. These results provide compelling evidence that OPC dysfunction may actually contribute to and exacerbate disease progression in AD. As such, the current study will investigate the impact of tau pathology and APOE genotype on abnormalities in OPCs and oligodendrocytes, including remyelination ability. In addition, given that deletion of the ApoE receptor, Lrp1, from OPCs provided neuroprotection, stimulated myelin repair and reduced inflammation in mouse models of demyelination, we will evaluate the protective effect of Lrp1 deficiency in OPCs in the context of tauopathy, as well as the role in exacerbation of tauopathy in the presence of ApoE4. Collectively, the current project will identify key functional and transcriptional alterations observed in the OPC/oligodendrocyte population in response to tauopathy and ApoE4, and determine whether loss of Lrp1 in OPCs mitigates ApoE4-mediated exacerbation of tau pathology.


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: 2025 ( Subtotal = $0 )
2025	2024	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Aging Research	001	3	8/21/2025	NON-COMPETING CONTINUATION	-$631,480
2025	2024	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Aging Research	003	3	9/27/2025	NON-COMPETING CONTINUATION	$0
2025	2024	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Aging Research	002	4	8/21/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$631,480
2025	2024	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Aging Research	000	3	3/27/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $631,481 )
2024	2024	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Aging Research	001	3	6/28/2024	NON-COMPETING CONTINUATION	$63,148
2024	2024	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Aging Research	000	3	3/8/2024	NON-COMPETING CONTINUATION	$568,333
														Subtotal = $631,481

Issue Date FY: 2023 ( Subtotal = $640,328 )
2023	2023	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Aging Research	001	2	6/30/2023	NON-COMPETING CONTINUATION	$0
2023	2023	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Aging Research	000	2	2/28/2023	NON-COMPETING CONTINUATION	$640,328
														Subtotal = $640,328

Issue Date FY: 2022 ( Subtotal = $542,019 )
2022	2022	MAYO CLINIC JACKSONVILLE (A NONPROFIT CORPORATION)	4500 SAN PABLO RD S	JACKSONVILLE	FL	32224	DUVAL	USA	Aging Research	000	1	5/25/2022	NEW	$542,019
														Subtotal = $542,019

Grand Total All Awards = $1,813,828

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Investigating tau and ApoE4-mediated alterations in oligodendrocyte progenitor cells

Award Number: R01AG071513

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2022

PERIOD OF PERFORMANCE END DATE: 05/18/2025

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