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 Ca(v)1.2 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 Ca(v)1.2 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 Ca(v)1.2 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
Ca(v)1.2 channel overexpression, the accumulation of hyperphosphorylated tau and suppression of autophagy in
Alzheimer's disease and modulation of this pathway by
isradipine.