# Testing the Calcium Hypothesis of Age-related Cognitive Decline

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $405,370

## Abstract

   
DESCRIPTION (provided by applicant): It is estimated that about 40% of people over the age of 65 suffer from some sort of age-related cognitive impairment that significantly impact quality of life. For many, these impairments will occur in the absence of overt clinical symptoms or neuropathology associated with Alzheimer's disease. While the exact cellular substrates that underlie these age-related alterations in cognition remain unknown, it has been previously shown that dysregulation of cytosolic free calcium ([Ca2+]i) homeostasis leads to altered neuronal function in aged animals. Furthermore, it has been suggested that one of the initial triggers for the sequelae of events that leads to altered calcium homeostasis is a paradoxical age-related increase in the expression of L-type voltage-gated calcium channels (LVGCCs). Furthermore, the increase in LVGCC expression has been correlated with decreased neuronal excitability and altered synaptic plasticity in aged animals. While these experiments suggest a correlation between age-related increases in LVGCC expression, learning deficits and altered neuronal function, it has yet to be demonstrated directly that increased LVGCC expression can actually disrupt neurocognitive function. Therefore, the primary objective of this proposal is to determine to what extent increased LVGCC expression impacts cognition and neuronal function. Our central hypothesis is that overexpression of LVGCCs can produce cognitive impairments and altered neuronal function in young mice similar to that which is observed during aging. Using a reverse genetics approach, we will test our central hypothesis directly by examining cognition and neuronal function in mice that have been genetically engineered to overexpress LVGCCs in the forebrain. Additionally, we propose to refine the current mouse model by generating two new transgenic lines that will provide greater regional and temporal specificity. The proposed experiments will provide us with valuable insight into the extent that dysregulation of intracellular calcium homeostasis contributes to age-related cognitive decline and will also provide a framework from which future investigations will advance targeted therapies intended to ameliorate cognitive impairments in the elderly.

## Key facts

- **NIH application ID:** 9873889
- **Project number:** 5R01AG052934-05
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** GEOFFREY G MURPHY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $405,370
- **Award type:** 5
- **Project period:** 2016-05-15 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9873889

## Citation

> US National Institutes of Health, RePORTER application 9873889, Testing the Calcium Hypothesis of Age-related Cognitive Decline (5R01AG052934-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9873889. Licensed CC0.

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