# L-type calcium channels in Alzheimer’s disease pathophysiology

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2024 · $592,588

## Abstract

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.

## Key facts

- **NIH application ID:** 10980207
- **Project number:** 1R01AG085531-01A1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Sarah Christine Hopp
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $592,588
- **Award type:** 1
- **Project period:** 2024-08-15 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10980207

## Citation

> US National Institutes of Health, RePORTER application 10980207, L-type calcium channels in Alzheimer’s disease pathophysiology (1R01AG085531-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10980207. Licensed CC0.

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