Levetiracetam ameliorated amyloidosis and tauopathy in mice with dexamethasone-induced Alzheimer’s disease

Abstract

Abstract Stress induced by glucocorticoids (GC), such as dexamethasone (DEX), has the potential to detrimentally impact the structure and function of the hippocampus and is closely associated with the development and progression of Alzheimer’s disease (AD). However, it remains uncertain whether LEV and TPM can effectively alleviate neuropathological and cognitive deficits in patients with DEX-induced AD by preserving or restoring neuronal network activities. This study aimed to investigate the mechanisms underlying the effect of DEX on AD development and progression and identify the role of NRP1 inflammasome in APP23/MAPTP301S mice. APP23/MAPTP301S mice were treated with DEX in the absence and presence of levetiracetam (LEV). After treatment, the mice were subjected to various cognitive and behavioral tests. DEX accelerated neuronal impairment by promoting the accumulation of β-amyloid protein and phosphorylation of tau in senile plaques and neurofibrillary tangles in APP23/MAPTP301S mice. Moreover, DEX significantly upregulated BACE1 and promoted the phosphorylation of cyclin-dependent kinase-5 and glycogen synthase kinase 3α/β, resulting in synaptic dystrophy and apoptosis. NLRP3 siRNA transfection showed that NLRP1 inflammasome activation is pivotal to the observed DEX effects. To counteract the adverse effects of DEX, LEV was administered to APP23/MAPTP301S mice, and it ameliorated DEX-induced AD via NLRP1-dependent mechanisms. This study underscores the detrimental impact of chronic glucocorticoid exposure on AD pathogenesis and the potential therapeutic benefits of compounds such as LEV in counteracting these effects by regulating neuroinflammation and key pathological markers.