L-type calcium channel antagonist isradipine age-dependently decreases plaque associated dystrophic neurites in 5XFAD mouse model

Abstract

Epidemiological studies suggest that L-type calcium channel (LTCC) antagonists may reduce the incidence of age-associated neurodegenerative diseases including Alzheimer's disease (AD). However, the neuroprotective mechanism of LTCC antagonists is unknown. Amyloid-β (Aβ) pathology disrupts intracellular calcium signaling, which regulates lysosomes and microglial responses. Neurons near Aβ plaques develop dystrophic neurites, which are abnormal swellings that accumulate lysosomes. Further, microglia accumulate around Aβ plaques and secrete inflammatory cytokines. We hypothesized that antagonism of LTCCs with isradipine would reduce Aβ plaque-associated dystrophic neurites and inflammatory microglia in the 5XFAD mouse model by restoring normal intracellular calcium regulation. To test this hypothesis, we treated 6- and 9-month-old 5XFAD mice with isradipine and tested behavior, examined Aβ plaques, microglia, and dystrophic neurites. We found that isradipine treatment age-dependently reduces dystrophic neurites and leads to trending decreases in Aβ but does not modulate plaque associated microglia regardless of age. Our findings provide insight into how antagonizing LTCCs alters specific cell types in the Aβ plaque environment, providing valuable information for potential treatment targets in future AD studies.