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Causes and consequences of differential APP processing in inhibitory and excitatory neurons

Award Number: R01AG085751
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2024
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Causes and consequences of differential APP processing in inhibitory and excitatory neurons - SUMMARY Alzheimer's disease (AD) was once considered a monolithic disorder of canonical symptoms and definitive pathology, but recent work has identified considerably heterogeneity in onset, progression, and histologic features. Despite this important shift in clinical perspective, we don't yet know if or how the range of brain pathologies explains the diversity in clinical trajectories. We also can't explain how neuropathological diversity arises in the first place, even for the canonical traits of amyloid, tangles, and neurodegeneration. It would be instructive to understand how such diverse structures arise and what if any role each plays in cognitive decline, but this insight has been stymied by human pathological heterogeneity combined with a paucity of appropriate animal models to replicate these extremes. We unexpectedly discovered a possible cellular explanation for the emergence of neuritic vs diffuse amyloid structures while characterizing two new transgenic lines that expressed the same APP construct selectively in glutamatergic or GABAergic neurons. Both models developed pronounced Ab deposits, but showed divergent patterns of pathology and Ab profiles. Glutamatergic APP mice formed cored, thioflavin-positive neuritic plaques composed of both Ab40 and 42, while GABAergic APP mice formed diffuse, thioflavin-negative plaques composed primarily of Ab42. These complementary APP transgenic models, with their respective diffuse and neuritic plaque pathology, now allow us to directly test the role of neuronal subtypes in plaque heterogeneity, identify the mechanistic basis for these differences in APP processing, and determine how distinct plaque structures may be pathogenic or protective through the divergent response of neighboring cells. Aim 1 will characterize the physical differences that distinguish plaques generated by GABAergic vs glutamatergic neurons using electron microscopy, in vivo seeding assays, and mass spectrometry. Aim 2 will determine how neuron-specific differences in APP processing arise using snRNAseq transcriptomic analysis of each neuronal subtype. This aim will also ascertain whether APP processing differences extend from overexpressed pathogenic APP to wild-type protein expressed at endogenous levels. Finally, Aim 3 will dissect the downstream consequences of each aggregate structure at the cell/molecular level using snRNAseq data and by testing cognitive function. Collectively we expect these studies may cast a new light on excitatory:inhibitory balance in AD and advance a new appreciation of neuronal heterogeneity as an important facet of disease pathogenesis.


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 = $0 )
2026	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Aging Research	000	2	11/25/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $596,328 )
2025	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Aging Research	002	2	8/21/2025	NON-COMPETING CONTINUATION	-$579,061
2025	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Aging Research	000	2	1/30/2025	NON-COMPETING CONTINUATION	$579,061
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Aging Research	003	3	8/21/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$544,855
2025	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Aging Research	001	2	7/28/2025	NON-COMPETING CONTINUATION	$51,473
														Subtotal = $596,328

Issue Date FY: 2024 ( Subtotal = $713,402 )
2024	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Aging Research	000	1	5/14/2024	NEW	$713,402
														Subtotal = $713,402

Grand Total All Awards = $1,309,730

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Causes and consequences of differential APP processing in inhibitory and excitatory neurons

Award Number: R01AG085751

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/15/2024

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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