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Synaptosomal MicroRNAs, Synaptic Damage and Cognitive Decline in Alzheimer's Disease

Award Number: R00AG065645
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Synaptosomal MicroRNAs, Synaptic Damage and Cognitive Decline in Alzheimer's Disease - Title. Synaptosomal MicroRNAs, Synaptic Damage and Cognitive Decline in Alzheimer's Disease Project summary/abstract The purpose of our study is to determine the role of synaptosomal microRNAs (miRNAs) in Alzheimer's disease (AD) progression and pathogenesis. Synapses are the most important compartments of neuron that deliver signals to adjacent neuron and maintain healthy synaptic functions of the brain. Synapse territories are composed of synaptic vesicles, synaptic proteins, mitochondria, neurotransmitters receptors, postsynaptic density protein and localized small RNAs and miRNAs. Recently, several studies identified the miRNAs enrichments at synapse, synaptic vesicles and synaptosomes. However, the role of synapse-associated miRNAs in AD progression is completely unexplored. In the first part of our study, we will identify the synaptosome-specific miRNAs that are deregulated in AD, and further, we will characterize their roles in AD progression and pathogenesis. Synaptosomal fraction will be extracted from frontal cortex region of postmortem brains from AD (n=15) and healthy controls (n=15). Total RNA will be extracted from synaptosomal fraction and processed for miRNA and mRNA sequencing. The deregulated synaptosome- specific miRNAs will be characterized in vitro using miRNA mimics and inhibitor(s) approaches and mutant APP and p-tau cDNA constructs. Impact of synaptosomal miRNAs will be studied against Aβ and p-tau induced toxicities. In second part we will determine the role of synaptosomal miRNAs in Aβ induced synaptic and cognitive dysfunction in AD. The impact of synaptosomal miRNAs will be studied on healthy neurons and AD neurons with Aβ induced toxicities. We will focus on neuronal processing, neuronal growth and network development and synaptic plasticity using APP primary neuronal cultures. Alteration of synaptosomal miRNAs expression and synaptic proteins will be studied with disease progression in APP transgenic (TG) and APP knockout (KO) mice. We will execute the synaptosome-specific miRNAs expression with various cognitive behavioral and biochemical tests in 2-, 6-, 12- and 18-month-old APP TG and APP KO mice lines relative to age-matched TG negative wild-type (WT) mice. And in third part we will study the role of synaptosomal miRNAs in phosphorylated-tau (p-tau) induced synaptic and cognitive dysfunction in AD. The impact of synaptosomal miRNAs will be studied on p-tau induced toxicity in neurons, healthy neurons processing, neuronal growth and network development and synaptic plasticity using tau primary neuronal culture. Alteration of synaptosomal miRNAs and synaptic proteins will be studied with disease progression in Tau TG and Tau KO mice. We will execute the synaptosome-specific miRNAs expression with various cognitive behavioral and biochemical tests in 2-, 6-, 12- and 18-month-old tau TG and KO mice relative to WT mice. Our study outcome will provide the answers for - 1) presence of synaptosomal miRNAs at AD synapse, 2) synaptosome- associated miRNAs linked with Aβ and p-tau pathologies in AD, 3) Overall synapse function, synaptic activity, assessment of therapeutic value of synaptosome-associated miRNAs in AD.


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 = -$4,980 )
2025	2024	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO	130 RICK FRANCIS ST	EL PASO	TX	79905	EL PASO	USA	Aging Research	001	5	8/6/2025	NON-COMPETING CONTINUATION	-$4,980
2025	2024	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO	130 RICK FRANCIS ST	EL PASO	TX	79905	EL PASO	USA	Aging Research	000	5	5/29/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = -$4,980

Issue Date FY: 2024 ( Subtotal = $371,116 )
2024	2024	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO	130 RICK FRANCIS ST	EL PASO	TX	79905	EL PASO	USA	Aging Research	002	5	5/24/2024	SUPPLEMENT FOR EXPANSION	$76,904
2024	2024	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO	130 RICK FRANCIS ST	EL PASO	TX	79905	EL PASO	USA	Aging Research	001	5	5/17/2024	NON-COMPETING CONTINUATION	$249,000
2024	2024	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO	5001 EL PASO DR	EL PASO	TX	79905	EL PASO	USA	Aging Research	000	4	10/31/2023	SUPPLEMENT FOR EXPANSION	$45,212
														Subtotal = $371,116

Issue Date FY: 2023 ( Subtotal = $249,000 )
2023	2023	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO	5001 EL PASO DR	EL PASO	TX	79905	EL PASO	USA	Aging Research	001	4	5/26/2023	NON-COMPETING CONTINUATION	$249,000
2023	2022	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO	5001 EL PASO DR	EL PASO	TX	79905	EL PASO	USA	Aging Research	000	3	2/27/2023	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $249,000

Issue Date FY: 2022 ( Subtotal = $292,046 )
2022	2022	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO	5001 EL PASO DR	EL PASO	TX	79905	EL PASO	USA	Aging Research	000	3	8/10/2022	EXTENSION WITH OR WITHOUT FUNDS	$249,000
2022	2022	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO	5001 EL PASO DR	EL PASO	TX	79905	EL PASO	USA	Aging Research	002	3	8/31/2022	EXTENSION WITH OR WITHOUT FUNDS	$43,046
2022	2022	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO	5001 EL PASO DR	EL PASO	TX	79905	EL PASO	USA	Aging Research	001	3	8/11/2022	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $292,046

Grand Total All Awards = $907,182

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Synaptosomal MicroRNAs, Synaptic Damage and Cognitive Decline in Alzheimer's Disease

Award Number: R00AG065645

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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