Neurosteroid-Mediated Neuroprotection via mTORC1/AMPK/BDNF Signaling Pathway in Alzheimer's Disease

Alzheimer's disease (AD) remains the leading cause of dementia worldwide. AD is a neurodegenerative disease associated with progressive synaptic dysfunction, neuronal loss, and cognitive impairment. Current pharmacological therapies for AD offer only symptomatic relief and fail to halt or reverse the progression of the disease. It has been shown that neurosteroids (NSs), the endogenous modulators synthesized within the central nervous system (CNS), have emerged as promising therapeutic candidates in the management of AD by regulating of neuronal function, synaptic plasticity, and neurogenesis. Growing evidence suggests that NSs, particularly allopregnanolone (AP) and related analogues, exert neuroprotective effects by attenuating amyloid-β (Aβ) accumulation, reducing tau hyperphosphorylation, restoring of mitochondrial function, and suppressing of neuroinflammation. Importantly, NSs modulate key intracellular pathways which implicated in AD pathogenesis, such as mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and brain-derived neurotrophic factor (BDNF). Interestingly, NSs attenuate Aβ- and tau-induced neurotoxicity and neurodegeneration by enhancing neuroprotective autophagy, activating AMPK/BDNF signaling, and suppressing the mTOR signaling pathway. However, the exact role of NSs in relation to the mTOR/AMPK/BDNF signaling axis in AD is not fully explained. Thus, this review synthesizes current knowledge on the molecular mechanisms through which NSs influence the mTORC1/AMPK/BDNF signaling axis, highlighting their therapeutic potential in mitigating AD neuropathology. Understanding the multifaceted actions of NSs may pave the way for novel neuroprotective strategies and future clinical interventions in AD management.