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Assessing Neuronal Vulnerability in the Entorhinal Cortex due to Alzheimer's Disease Pathology

Award Number: R21AG089715
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2024
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Assessing Neuronal Vulnerability in the Entorhinal Cortex due to Alzheimer's Disease Pathology - PROJECT SUMMARY Understanding how specific neurons in a selectively vulnerable region such as the EC are affected is critical to unraveling the mechanisms underlying Alzheimer's disease onset. We and others have shown that neuronal hyperexcitability is the key driver that makes pathologies and symptoms worse and ameliorating hyperexcitability slows down AD-related symptoms. However, it is unclear if the hyperexcitability is due to an increased firing of excitatory neurons or decreased firing of inhibitory neurons. We aim to understand the mechanisms underlying hyperexcitability by studying the excitatory and inhibitory neurons in the EC of App and tau knockin mice. To determine which type of neurons are affected early in the EC, we will investigate: Aim 1- Excitatory neurons in the App knockin (AppNL-G-F) and tau knockin (hTau-KI) mice by using intersectional approach with optogenetics and chemogenetics in combination with electrophysiology recordings and behavior and Aim 2- Inhibitory neurons (parvalbumin- PV and somatostatin- SST) in the AppNL-G-F and hTau-KI mice as in aim 1. Using Cre-specific mice to target excitatory and inhibitory neurons in combination with opto- or chemo- genetic approach we will not only identify selectively vulnerable neuron-type, but we will also modulate their activities to restore their function and test if behavioral deficits are reversed. We will use novel computational approaches such as decoding and remapping to detect subtle changes in firing activity of EC neurons. We will also assess how amyloid beta or tau affect different neuron types in the EC, and if downstream hippocampal neurons are affected too. The results of the proposal will definitively answer if hyperexcitability of neurons due to AD pathologies is caused by dysfunction of excitatory or inhibitory neurons. The sensitive computational methods used in this proposal allow for measurement of subtle electrophysiological changes not possible previously and therefore might allow for development of better diagnostic tests that could be translated and modified for clinical use in humans. Overall, the proposal aims to identify which neurons in the MEC are most vulnerable to AD pathology. The proposal is highly innovative as it will use a combination of sophisticated in vivo recording in two AD mouse models in combination with optogenetic and chemogenetic tools to identify specific cell type and modulate neuronal firing to restore function. The results from the study will be highly significant as therapeutic or clinical approaches to target vulnerable cell type could be identified. The proposal brings together diverse fields (electrophysiology, pathology and computational neuroscience) applying large-scale recording techniques to record ensemble populations of neurons to interrogate what causes hyperexcitability in a vulnerable brain region that is dysfunctional in Alzheimer’s disease.


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	THE 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	4/7/2025	NEW	$0
2025	2024	THE WINIFRED MASTERSON BURKE MEDICAL RESEARCH INSTITUTE, INC	785 MAMARONECK AVE	WHITE PLAINS	NY	10605	WESTCHESTER	USA	Aging Research	003	2	4/7/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2025	2024	THE WINIFRED MASTERSON BURKE MEDICAL RESEARCH INSTITUTE, INC	785 MAMARONECK AVE	WHITE PLAINS	NY	10605	WESTCHESTER	USA	Aging Research	001	2	3/12/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$378,793
2025	2024	THE 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	3/11/2025	NEW	-$378,793
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $452,375 )
2024	2024	THE 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	7/25/2024	NEW	$401,654
2024	2024	THE 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	001	1	8/6/2024	NEW	$50,721
														Subtotal = $452,375

Grand Total All Awards = $452,375

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Assessing Neuronal Vulnerability in the Entorhinal Cortex due to Alzheimer's Disease Pathology

Award Number: R21AG089715

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2024

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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