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Metabolic syndrome impairs oligodendrocyte metabolic support of neurons leading to Alzheimer’s disease/Alzheimer’s disease and related dementias

Award Number: R00AG081390
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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Metabolic syndrome impairs oligodendrocyte metabolic support of neurons leading to Alzheimer’s disease/Alzheimer’s disease and related dementias - ABSTRACT Alzheimer’s disease (AD) and AD-related Dementia (ADRD) constitute the main cause of dementia and mani- fest as an array of symptoms and signs, including impaired cognition and poor memory. AD/ADRD poses a substantial socioeconomic burden, with dementia affecting 1 of 9 people aged 65 and older in 2021 in the United States (US) and direct healthcare costs estimated at $355 billion USD. AD/ADRD currently lacks effec- tive disease-modifying treatments, though multiple AD/ADRD risk factors have been identified, including midlife metabolic syndrome (MetS) and its components, such as diabetes, obesity, and dyslipidemia. Recent preclini- cal and clinical research reveals that AD/ADRD and cognitive impairment associated with MetS progress non- cell autonomously in the brain through a concerted breakdown in oligodendrocyte function with resulting neu- ronal loss. However, there is a gap in our understanding of how MetS and its associated oligodendrocyte dys- function leads to cognitive impairment and AD/ADRD. Given the increasing burden of AD/ADRD and MetS, there is a critical need to identify the mechanisms of oligodendrocyte-neuron metabolic crosstalk and its role in MetS leading to AD/ADRD. Our proposal will elucidate how midlife MetS onset disrupts oligodendrocyte me- tabolism and consequent support to neurons, leading to AD/ADRD in later life. Under physiological conditions, oligodendrocytes metabolically support neurons with lactate shuttled via monocarboxylate transporter 1 (MCT1). This ensures an adequate energy substrate supply to neurons, supporting normal cognitive function. Two crucial pieces of data are relevant to this proposal. First, the MetS influences epigenetic elements that de- crease MCT1 expression. Second, AD/ADRD is associated with oligodendrocyte loss, reduced cerebral lac- tate, and neuronal injury. Our objective therefore is to elucidate the role of oligodendrocyte-neuron metabolic crosstalk and the lactate shuttle in the MetS leading to AD/ADRD with aging. Our central hypothesis is that MetS disrupts oligodendrocyte-neuron metabolic crosstalk, impairing the lactate shuttle, leading to loss of met- abolic support to neurons, ultimately promoting AD/ADRD. We will test our hypothesis by: 1) assessing the ef- fects of MetS on cognition and oligodendrocytes epigenomics and transcriptomics in middle-aged mice, 2) evaluating oligodendrocyte-neuron metabolic crosstalk in an in vitro MetS model, and 3) assessing the impact of targeting the oligodendrocyte lactate shuttle on cognition in middle-aged MetS mice. This study will have a significant impact by elucidating the contribution of oligodendrocyte metabolic support to neurons, particularly via the lactate shuttle, in MetS-associated AD/ADRD, and further examine oligodendrocyte MCT1 as a novel therapeutic target for MetS-associated AD/ADRD. These studies will support our long-term goal of identifying and implementing novel, translatable interventions for MetS-induced AD/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: 2026 ( Subtotal = $249,000 )
2026	2026	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Aging Research	000	3	6/16/2026	EXTENSION WITH OR WITHOUT FUNDS	$249,000
														Subtotal = $249,000

Grand Total All Awards = $249,000

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Metabolic syndrome impairs oligodendrocyte metabolic support of neurons leading to Alzheimer’s disease/Alzheimer’s disease and related dementias

Award Number: R00AG081390

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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