Pharmacological modulation of autophagy for Alzheimer's disease therapy:Opportunities and obstacles

Alzheimer's disease(AD)is a prevalent and deleterious neurodegenerative disorder characterized by an irreversible and progressive impairment of cognitive abilities as well as the formation of amyloidβ(Aβ)plaques and neurofibrillary tangles(NFTs)in the brain.By far,the precise mechanisms of AD are not fully understood and no interventions are available to effectively slow down progression of the disease.Autophagy is a conserved degradation pathway that is crucial to maintain cellular homeostasis by targeting damaged organelles,pathogens,and disease-prone protein aggregates to lysosome for degradation.Emerging evidence suggests dysfunctional autophagy clearance pathway as a potential cellular mechanism underlying the pathogenesis of AD in affected neurons.Here we summarize the current evidence for autophagy dysfunction in the pathophysiology of AD and discuss the role of autophagy in the regulation of AD-related protein degradation and neuroinflammation in neurons and glial cells.Finally,we review the autophagy modulators reported in the treatment of AD models and discuss the obstacles and opportunities for potential clinical application of the novel autophagy activators for AD therapy.

Noncanonical autophagy in systemic lupus erythematosus

Background:Noncanonical autophagy is generally described as a lysosomal degradation process that requires only a subset of the core autophagy-related proteins to form functional autophagosomes.Review:Accumulating evidence implicates noncanonical autophagy pathways in expanding the versatility of the immune system via regulation of functions that include antigen presentation,dead cell clearance,inflammatory cytokine production,and immune cell homeostasis.In this review,we use microtubuleassociated protein 1 light chain 3-associated phagocytosis(LAP)as an example of noncanonical autophagy,describing its distinctive molecular machinery and highlighting recent advances in its functioning in immunity.We also discuss the direct and indirect evidence supporting the pathogenic significance of abnormal levels of LAP in systemic lupus erythematosus(SLE).Future Perspectives:A better understanding of the role of noncanonical autophagy in SLE may reveal crucial information about the disease pathology,providing direction for therapeutic developments and improved prognosis.