Therapeutic Effects of Aripiprazole in the 5xFAD Alzheimer’s Disease Mouse Model

Abstract

Global aging has led to growing health concerns posed by Alzheimer’s disease (AD), the most common type of dementia. Aripiprazole is an atypical FDA-approved anti-psychotic drug with potential against AD. To investigate its therapeutic effects on AD pathology, we administered aripiprazole to 5xFAD AD model mice and examined beta-amyloid (βA)-induced AD-like phenotypes, including βA production, neuroinflammation, and cerebral glucose metabolism. Aripiprazole administration significantly decreased βA accumulation in the brains of 5xFAD AD mice. Aripiprazole significantly modified amyloid precursor protein processing, including carboxyl-terminal fragment β and βA, a disintegrin and metalloproteinase domain-containing protein 10, and beta-site APP cleaving enzyme 1, as determined by Western blotting. Neuroinflammation, as evidenced by ionized calcium binding adapter molecule 1 and glial fibrillary acidic protein upregulation was dramatically inhibited, and the neuron cell layer of the hippocampal CA1 region was preserved following aripiprazole administration. In 18F-fluorodeoxyglucose positron emission tomography, after receiving aripiprazole, 5xFAD mice showed a significant increase in glucose uptake in the striatum, thalamus, and hippocampus compared to vehicle-treated AD mice. Thus, aripiprazole effectively alleviated βA lesions and prevented the decline of cerebral glucose metabolism in 5xFAD AD mice, suggesting its potential for βA metabolic modification and highlighting its therapeutic effect over AD progression.

Chronic Aripiprazole and Trazodone Polypharmacy Effects on Systemic and Brain Cholesterol Biosynthesis

“…ARI treatment in several rodent models led to decreased IBA1 protein expression [ 23 , 24 , 40 ]. IBA1 protein is specifically expressed in brain microglia and macrophages and is upregulated during their activation [ 45 ].…”

“…Studies in rodents have shown that both ARI and TRZ affect brain tissue through unique signaling pathways and their effects are not always directly related to their binding on dopaminergic and serotonergic receptors [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. ARI has been shown to have neuroprotective effects in stroke recovery by promoting dopaminergic survival and neuroprotective effects in a mouse model of Alzheimer’s Disease [ 23 , 24 ]. While many studies using rodent models have shown the therapeutic effects of ARI and TRZ in different pathological conditions, there are limited reports describing their biochemical effects in healthy mice.…”

Amylin and Secretases in the Pathology and Treatment of Alzheimer’s Disease

“…However, there is some promise in utilizing the lipid-lowering medication gemfibrozil which activates PPAR-α and was shown to both inhibit the production of Aβ via upregulation of ADAM10 and stimulate cellular clearance by inducing lysosomal biogenesis in the 5XFAD transgenic model of AD [33][34][35][36][37]. In a phase II parallel-design, double-blind, placebo-controlled trial targeting predementia AD, there was a significant decline on the CANS-MCI cognitive battery, and almost statistically significant declines in Aβ 42 levels and hippocampal atrophy [38].…”