Protective function of StAR in amyloid-β accumulated hippocampal neurotoxicity and neurosteroidogenesis: Mechanistic insights into Alzheimer's disease

The steroidogenic acute regulatory (StAR) protein principally mediates steroid hormone biosynthesis by governing the transport of intramitochondrial cholesterol. Neurosteroids progressively decrease during aging, the key risk factor for Alzheimer's disease (AD), which is triggered by brain-region specific accumulation of amyloid beta (Aβ) precursor protein (APP), a key pathological factor. We demonstrate that hippocampal neuronal cells overexpressing wild-type (WtAPP) and mutant APP (mAPP) plasmids, conditions mimetic to AD, resulted in decreases in StAR mRNA, free cholesterol, and pregnenolone levels. The magnitude of suppression of the steroidogenic response was more pronounced with mAPP than that of WtAPP. While mAPP-waned assorted anomalies correlate to AD pathology, deterioration of APP/Aβ laden StAR expression and neurosteroid biosynthesis was enhanced by retinoid signaling. An abundance of mitochondrially targeted StAR expression partially restored APP/Aβ accumulated diverse neurodegenerative vulnerabilities. Immunofluorescence analyses revealed that overexpression of StAR diminishes mAPP provoked Aβ aggregation. Co-expression of StAR and mAPP in hippocampal neurons substantially reversed the declines in mAPP mediated cell survival, mitochondrial oxygen consumption rate, and ATP production. Concurrently, induction of mAPP induced Aβ loading showed an increase in cholesterol esters, but decrease in free cholesterol, concomitant with pregnenolone biosynthesis, events that were inversely regulated by StAR. Moreover, retinoid signaling was found to augment cholesterol content for facilitating neurosteroid biosynthesis in an AD mimetic condition. These findings provide novel insights into the molecular events by which StAR acts to protect mAPP-induced hippocampal neurotoxicity, mitochondrial dysfunction, and neurosteroidogenesis, and these measures are fundamental for ameliorating and/or delaying dementia in individuals with AD.