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

Abstract

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.

Figure 1

A schematic overview of the Aβ-Ca_v1.2-ptau-autophagy pathway. Three sections of the figure are separated by dashed lines for clarity. Soluble Aβ oligomers, soluble and insoluble Aβ fibrils generated from amyloid precursor protein (APP) processing cause increased expression of Ca_v1.2 through beta 2 adrenergic receptor (β2AR)/cyclin AMP (cAMP) or other unknown pathways (section 1). Aβ production can be directly modulated by mutations in the calcium homeostasis modulator 1 (CALHM1) receptor located on the endoplasmic reticulum, or in response to treatment with dihydropyridine (DHP) class of calcium channel blockers (CCBs) (section 2). Intracellular or extracellular Aβ can cause over-expression of cav1.2, increased influx of Ca², disrupted autophagy, and up-regulated ptau expression (section 3). Ca²⁺-calpain pathway can directly increase ptau levels or dampen autophagy function. Pathological accumulation of autophagosomal vacuoles and ptau will lead to loss of spatial memory and cognition in AD (section 3). Isradipine (ISR) appears to block this pathway.