Oral nimodipine treatment has no effect on amyloid pathology or neuritic dystrophy in the 5XFAD mouse model of amyloidosis

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.

APOE genotype and biological sex regulate astroglial interactions with amyloid plaques in Alzheimer’s disease mice

“…S3). We subsequently addressed plaque-associated LAMP1 labeling, a lysosomal marker known to exhibit high expression in plaque-associated DNs [21][22][23][24]. LAMP1 was used to establish whether astroglial plaque coverage was associated with neurite dystrophy.…”

Angiotensin II Receptor Blockers Reduce Tau/Aß42 Ratio: A Cerebrospinal Fluid Biomarkers’ Case-Control Study

“…In other matters, CCB highlights promising results in dementia prevention [ 15 , 22 , 23 , 24 ]. Intracellular calcium is elevated in elderly patients and plays a part in neurodegeneration, amyloid production enhancement, and tau hyperphosphorylation [ 15 , 16 , 23 , 46 ]. Thus, CCB may downregulate intracellular calcium levels and slow amyloid production [ 16 , 23 ].…”

“…Thus, CCB may downregulate intracellular calcium levels and slow amyloid production [ 16 , 23 ]. In addition, CCB can enhance cerebral vascularization [ 15 ] and, in the case of nimodipine, can act as a cerebral vasodilator [ 46 ]. Among CCB, the dihydropyridine compounds stand out with promising results in Aß42 clearance [ 21 , 23 ].…”

“…Moreover, just one patient took nimodipine when the lumbar puncture was performed. A recent study by Sadleir Id and colleagues aimed to explore whether nimodipine could modify amyloid pathogenesis when it begins in mouse models, but it did not show any changes in the Aß42 or total Aß levels nor amyloid plaque deposition [ 46 ]. In addition, it was shown in work performed by Murray and colleagues in 2002 that CCBs were not associated with dementia prevention.…”

Therapeutic Potential of Heterocyclic Compounds Targeting Mitochondrial Calcium Homeostasis and Signaling in Alzheimer’s Disease and Parkinson’s Disease

“…[424] Sadleir et al showed that oral administration of nimodipine to 5XFAD mice did not have a beneficial effect on amyloid pathology, since the molecule did not prevent neuritic dystrophy or reduce cortical or hippocampal Aβ content. [425] However, the treatment did not exacerbate the AD phenotype, suggesting a safety and tolerability profile. It has been described that iron uptake, which competes with Ca 2+ for entry into neurons through the L-type VOCCs, can be inhibited with nimodipine in a dose-dependent fashion in potassium chloride stimulated neuronal cells.…”