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.