Calcium channel blocking as a therapeutic strategy for Alzheimer's disease: The case for isradipine

Alzheimer's disease is the most devastating neurodegenerative disorder in the elderly, yet treatment options are severely limited. The drug development effort to modify Alzheimer's disease pathology by intervention at beta amyloid production sites has been largely ineffective or inconclusive. The greatest challenge has been to identify and define downstream mechanisms reliably predictive of clinical symptoms. Beta amyloid accumulation leads to dysregulation of intracellular calcium by plasma membrane L-type calcium channels located on neuronal somatodendrites and axons in the hippocampus and cortex. Paradoxically, L-type calcium channel subtype Cav1.2 also promotes synaptic plasticity and spatial memory. Increased intracellular calcium modulates amyloid precursor protein processing and affects multiple downstream pathways including increased hyperphosphorylated tau and suppression of autophagy. Isradipine is a Federal Drug Administration-approved dihydropyridine calcium channel blocker that binds selectively to Cav1.2 in the hippocampus. Our studies have shown that isradipine in vitro attenuates beta amyloid oligomer toxicity by suppressing calcium influx into cytoplasm and by suppressing Cav1.2 expression. We have previously shown that administration of isradipine to triple transgenic animal model for Alzheimer's disease was well-tolerated. Our results further suggest that isradipine became bioavailable, lowered tau burden, and improved autophagy function in the brain. A better understanding of brain pharmacokinetics of calcium channel blockers will be critical for designing new experiments with appropriate drug doses in any future clinical trials for Alzheimer's disease. This review highlights the importance of Cav1.2 channel overexpression, the accumulation of hyperphosphorylated tau and suppression of autophagy in Alzheimer's disease and modulation of this pathway by isradipine.

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► Aβ neurotoxicity leads to intracellular calcium influx and vice versa.
► Intracellular calcium influx occurs via Cav1.2 channels.
► Calcium influx further leads to increased hyperphosphrylated tau and autophagy dysfunction.
► L-type voltage-gated calcium channel blockers prevent neurotoxicity associated with intracellular Aβ and calcium.
► Isradipine appears to be a potent calcium channel blocker.