Sigma ligands as potent inhibitors of Aβ and AβOs in neurons and promising therapeutic agents of Alzheimer's disease

Alzheimer's disease (AD) is an age-related neurodegenerative disease and characterized by dementia, memory decline, loss of learning and cognitive disorder. The main pathological features of AD are the deposition of amyloid plaques and the formation of neurofibrillary tangles (NFTs) in the brain. The current anti-AD drugs have shown unsatisfactory therapeutic results. Due to the complications and unclear pathogenesis, AD is still irreversible and incurable. Among several hypotheses proposed by the academic community, the amyloid cascade is widely recognized by scholars and supported by a large amount of evidences. However, controversy over pathogenic factors has also been ongoing. Increasing evidence has shown that amyloid-β (Aβ) and especially amyloid-β oligomers (AβOs) are highly neurotoxic and pathogenic agents that damage neurons, mediate various receptors in the downstream pathways, and ultimately lead to learning and cognitive dysfunction. However, efforts in developing inhibitors of Aβ or amyloid-β precursor protein (APP) have all failed to yield good clinical results. More recently, it has been demonstrated that sigma receptors, including sigma-1 and sigma-2 subtypes, may play critical roles in the regulation of binding and metabolism of AβOs in neuron cells and the pathophysiology of AD. Thus, sigma receptor ligands are being recognized as promising therapeutic agents for treating or ameliorating AD. This article will review the pathophysiology of AD and highlight the sigma ligands that display the capability of preventing or even reversing Aβ- and AβOs-induced neurotoxicity and blocking the signal transduction caused by AβOs.