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Role of the microglial immune-oxysterol 25-hydroxycholesterol in mediating neuroinflammation and neurodegeneration in the P301S tau transgenic mouse model of Alzheimer's disease

Award Number: R01AG081419
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT Alzheimer disease (AD) is the most common neurodegenerative disorder characterized by neuroinflammation associated with amyloid plaques and tau-containing neurofibrillary tangles in the brain as well as severe neurodegeneration, neuroinflammation and lipid accumulation. The apolipoprotein E (APOE) genotype is by far the most powerful genetic risk factor for late-onset AD and is thought to play an important role in neuroinflammation and lipid metabolism. Pathological activation of microglia and astrocytes contribute substantially to the loss of neurons and synapses and lipid dysfunction in AD and related dementias (ADRD). Despite an important pathogenic role for microglia in tau-mediated neurodegeneration, the specific microglial mediators of neuroinflammation and neurodegeneration are poorly understood. Our lab has recently demonstrated that the microglial immune-oxysterol 25-hydroxycholesterol (25HC) augments the production of the proinflammatory cytokine, IL-1b, in an APOE-isoform dependent manner (E4>E3). Cholesterol 25- hydroxylase (CH25H), the enzyme that synthesizes 25HC is upregulated in AD and PS19 brain tissue as well as in disease-associated microglia (DAM). We have preliminary evidence that 25HC directly contributes to the age-dependent neurodegeneration observed in PS19 mice and regulates cholesterol metabolism in astrocytes. We hypothesize that 25HC synthesized and secreted by activated microglia drives tau-dependent neuroinflammation and neurodegeneration via its effects in regulating cholesterol metabolism. We will test this hypothesis as follows – In Aim 1, we will determine the importance of Ch25h in mediating tau-dependent neuroinflammation and neurodegeneration. In Aim 2, we will determine the role of Ch25h/25HC in mediating the deleterious effects of APOE4 on tau-dependent neuropathology. In Aim 3, we will determine whether and how 25HC alters cholesterol metabolism to reduce neuronal viability. Successful completion of this project may enable the development of novel therapeutic strategies towards ADRD.


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 = $466,366 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Aging Research	000	2	4/18/2024	NON-COMPETING CONTINUATION	$466,366
														Subtotal = $466,366

Issue Date FY: 2023 ( Subtotal = $477,725 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Aging Research	000	1	5/4/2023	NEW	$477,725
														Subtotal = $477,725

Grand Total All Awards = $944,091

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Role of the microglial immune-oxysterol 25-hydroxycholesterol in mediating neuroinflammation and neurodegeneration in the P301S tau transgenic mouse model of Alzheimer's disease

Award Number: R01AG081419

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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