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L-type calcium channels in Alzheimer’s disease pathophysiology

Award Number: R01AG085531
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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L-type calcium channels in Alzheimer’s disease pathophysiology - Abstract The calcium hypothesis of Alzheimer’s disease (AD) links calcium dysregulation and the amyloidogenic pathway to cognitive dysfunction and tau pathology in AD. Calcium dysregulation occurs in many cell types during Alzheimer’s disease. One potential source of dysregulated calcium during AD is L-type calcium channels (LTCCs). We have found that LTCC antagonists can reduce endo-lysosomal dysfunction around amyloid plaques during Alzheimer’s disease and can ameliorate microglia dysregulation during chronic neuroinflammation. There is significant crosstalk between these two pathways, suggesting that LTCC antagonists can target both microglia and neurons, mediating complementary and age-dependent neuroprotection during AD pathology. Notably, the non-brain-penetrant LTCC antagonist amlodipine is associated with reduced risk for AD neuropathology and cognitive deficits, suggesting a role for brain-periphery crosstalk contributing to LTCC antagonist mediated neuroprotection during AD pathology. The overall goal of our proposed research is to determine how LTCC antagonists may mediate their neuroprotective effects in the context of amyloid pathology. In Aim 1, we will evaluate the contribution of neuronal Cav1.2 and Cav1.3 LTCCs to endo-lysosomal dysfunction during amyloid pathology using conditional neuron-specific knockout mice. In Aim 2, we will evaluate the contributions of microglial Cav1.2 and Cav1.3 LTCCs to endo-lysosomal dysfunction during amyloid pathology using microglia-specific conditional knockout mice. In Aim 3, we will evaluate the peripheral contribution of LTCC antagonists to neuroprotection during AD pathology using brain-penetrant and non-brain-penetrant LTCC antagonists. Overall, these studies will enhance our current understanding of LTCCs as mediators of calcium dysregulation during AD pathology and the beneficial role of LTCC antagonists on different neural cells and peripheral contributions. In turn, understanding which LTCC subunits to target and how to best target lays the groundwork for future clinical trials repurposing LTCC antagonists for AD and other neurodegenerative disorders.


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 = $563,501 )
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Aging Research	000	2	5/7/2025	NON-COMPETING CONTINUATION	$517,501
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Aging Research	001	2	6/17/2025	NON-COMPETING CONTINUATION	$46,000
														Subtotal = $563,501

Issue Date FY: 2024 ( Subtotal = $592,588 )
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Aging Research	000	1	8/2/2024	NEW	$592,588
														Subtotal = $592,588

Grand Total All Awards = $1,156,089

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L-type calcium channels in Alzheimer’s disease pathophysiology

Award Number: R01AG085531

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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