Abstract
Dysregulation of calcium homeostasis has been hypothesized to play a role in Alzheimer’s disease (AD) pathogenesis. Increased calcium levels can impair axonal transport, disrupt synaptic transmission, and ultimately lead to cell death. Given the potential role of calcium dyshomeostasis in AD, there is interest in testing the ability of already approved drugs targeting various calcium channels to affect amyloid pathology and other aspects of disease. The objective of this study was to test the effects of FDA-approved L-type calcium channel antagonist nimodipine on amyloid accumulation and dystrophic neurite formation in 5XFAD mice, a mouse model of amyloid pathology. 5XFAD transgenic mice and non-transgenic littermates were treated with vehicle or nimodipine-containing chow from two to eight months of age, then brains were harvested and amyloid pathology assessed by immunoblot and immunofluorescence microscopy analyses. Nimodipine was well tolerated and crossed the blood brain barrier, as expected, but there was no effect on Aβ accumulation or on the relative amount of neuritic dystrophy, as assessed by either immunoblot, dot blot or immunofluorescence imaging of Aβ42 and dystrophic neurite marker LAMP1. While we conclude that nimodipine treatment is not likely to improve amyloid pathology or decrease neuritic dystrophy in AD, it is worth noting that nimodipine did not worsen the phenotype suggesting its use is safe in AD patients.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disease of the elderly and causes irreversible memory loss and behavioral changes, leading to death [1,2], and, with the possible exception of aducanumab/Aduhelm, there are no disease modifying therapeutics available
Male and female 5XFAD mice and non-transgenic littermates were fed chow containing 300 ppm nimodipine starting at 9 weeks of age, which corresponds with the early stage of amyloid deposition [31]
At 8 months of age, y-maze and fear conditioning behavioral tests were performed to test for effects on learning and memory, but no significant differences were found between non-Tg and 5XFAD on Y-maze or fear conditioning, limiting our ability to draw conclusions about the effects of nimodipine on cognition in the context of amyloid pathology (S1 Fig)
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disease of the elderly and causes irreversible memory loss and behavioral changes, leading to death [1,2], and, with the possible exception of aducanumab/Aduhelm, there are no disease modifying therapeutics available. The two main pathological hallmarks of AD are extracellular amyloid plaques, composed of aggregated Aβ peptides, and intracellular neurofibrillary tangles composed of hyperphosphorylated tau [1,2]. Aβ peptides are generated by the sequential cleavages of the amyloid precursor protein (APP) by the β-secretase, BACE1 [3,4,5,6], followed by γ-secretase. Oral nimodipine treatment has no effect on amyloid pathology analysis, decision to publish, or preparation of the manuscript
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