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Synergy in Condensation: Tau and Aβ in Alzheimer's Disease

Award Number: F32AG099737
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/01/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2029

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Synergy in Condensation: Tau and Aβ in Alzheimer's Disease - Project Summary Alzheimer’s disease (AD) is the leading cause of dementia, affecting over 6.7 million people in the United States, yet the mechanisms underlying its pathology remain incompletely understood. In virtually every case of AD, extracellular amyloid-beta (Aβ) plaques and intracellular Tau neurofibrillary tangles co-occur, suggesting significant interplay between these two proteins. Although a direct link between Aβ plaque formation and Tau tangle deposition is still being elucidated, recent evidence indicates that soluble, intracellular Aβ oligomers can bind Tau and promote its aggregation. Both Aβ and Tau are intrinsically disordered proteins that undergo liquid– liquid phase separation (LLPS), forming protein-dense biomolecular condensates that can either facilitate physiological function or propagate pathological aggregation in neurons. Our preliminary data show that Tau condensates can adopt either a physiological state, recruiting tubulin to stabilize microtubules and resist aberrant aggregation, or a pathological one, where Aβ recruitment triggers fibril formation. Accordingly, we seek to characterize how Tau:Aβ interactions within condensates drive pathological aggregation, clarifying the kinetics of oligomeric species formation and identifying potential therapeutic targets. Additionally, we will determine whether reinforcing functional Tau:tubulin interactions can prevent or reverse the formation of pathogenic Tau:Aβ assemblies. In Aim 1, I will define how Aβ alters the structural properties of Tau condensates to drive pathological aggregation. Specifically, I will employ advanced biophysical techniques, including fluorescence lifetime imaging microscopy (FRET-FLIM) and microfluidic modulation infrared spectroscopy (MMS), to investigate whether Aβ accelerates Tau oligomerization within condensates and promotes β-sheet–rich, aggregation-prone structures. I will also delineate how these protein assemblies within condensates differ in kinetics and stability from analogous reactions occurring in dilute conditions. In Aim 2, I will determine whether tubulin can rescue Tau from this Aβ-driven pathology by reinforcing physiological Tau:tubulin interactions. Using an optogenetic system in neuronal cell lines, I will manipulate tubulin levels genetically and pharmacologically to test how tubulin enrichment affects Aβ-driven Tau aggregation, as measured by high-molecular-weight oligomers and hyperphosphorylated Tau. I will extend these findings to patient-derived induced pluripotent stem cell (iPSC) neurons to validate whether tubulin stabilization similarly protects against endogenous Tau pathology in a disease-relevant context. Upon completion of these studies, I will have established a mechanistic framework for how intracellular Aβ accelerates Tau aggregation via condensates, and how tubulin might mitigate this transition. These insights will contribute to our understanding of early-stage AD pathology and may inform future therapeutic strategies aimed at preserving or restoring physiological condensate function.


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 = $76,300 )
2026	2026	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Aging Research	000	1	6/30/2026	NEW	$76,300
2026	2026	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Aging Research	001	1	6/30/2026	NEW	$0
														Subtotal = $76,300

Grand Total All Awards = $76,300

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Synergy in Condensation: Tau and Aβ in Alzheimer's Disease

Award Number: F32AG099737

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/01/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2029

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