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...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.展开更多
Neuroinflammation and neurodegeneration are key components in the establishment and progression of neurodegenerative diseases including Alzheimer's Disease(AD). Over the past decade increasing evidence is emerging...Neuroinflammation and neurodegeneration are key components in the establishment and progression of neurodegenerative diseases including Alzheimer's Disease(AD). Over the past decade increasing evidence is emerging for the use of components of the canonical autophagy machinery in pathways that are characterized by LC3 lipidation yet are distinct from traditional macro-autophagy. One such pathway that utilizes components of the autophagy machinery to target LC3 to endosomes, a process termed LC3-associated endocytosis(LANDO), has recently been identified and regulates neuroinflammation. Abrogation of LANDO in microglia cells results in a propensity for elevated neuroinflammatory cytokine production. Using the well-established 5 xFAD model of AD to interrogate neuroinflammatory regulation, impairment of LANDO through deletion of a key upstream regulator Rubicon or other downstream autophagy components, exacerbated disease onset and severity, while deletion of microglial autophagy alone had no measurable effect. Mice presented with robust deposition of the neurotoxic AD protein β-amyloid(Aβ), microglial activation and inflammatory cytokine production, tau phosphorylation, and aggressive neurodegeneration culminating in severe memory impairment. LANDO-deficiency impaired recycling of receptors that recognize Aβ, including TLR4 and TREM2. LANDO-deficiency alone through deletion of the WD-domain of the autophagy protein ATG16 L, revealed a role for LANDO in the spontaneous establishment of age-associated AD. LANDO-deficient mice aged to 2 years presented with advanced ADlike disease and pathology correlative to that observed in human AD patients. Together, these studies illustrate an important role for microglial LANDO in regulating CNS immune activation and protection against neurodegeneration. New evidence is emerging that demonstrates a putative linkage between pathways such as LANDO and cell death regulation via apoptosis and possibly necroptosis. Herein, we provide a review of the use of the autophagy machinery 展开更多
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 evid...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.展开更多
基金This study was supported by China minister of Science and Technology grant MoST-2017YFE0120100the Science and Technology Development Fund,Macao SAR(No.0110/2018/A3,0128/2019/A3,China)+1 种基金the University of Macao grants(No.MYRG2019-00129-ICMS,China)awarded to Jia-Hong LuNIH/R01NS060123 and R01 R01AG072520(USA)awarded to Zhenyu Yue.
文摘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.
基金supported in part by the funding from the National Institute of Allergy and Infectious Disease and the National Cancer Institute under award numbers AI138492 and CA231423 to BLH。
文摘Neuroinflammation and neurodegeneration are key components in the establishment and progression of neurodegenerative diseases including Alzheimer's Disease(AD). Over the past decade increasing evidence is emerging for the use of components of the canonical autophagy machinery in pathways that are characterized by LC3 lipidation yet are distinct from traditional macro-autophagy. One such pathway that utilizes components of the autophagy machinery to target LC3 to endosomes, a process termed LC3-associated endocytosis(LANDO), has recently been identified and regulates neuroinflammation. Abrogation of LANDO in microglia cells results in a propensity for elevated neuroinflammatory cytokine production. Using the well-established 5 xFAD model of AD to interrogate neuroinflammatory regulation, impairment of LANDO through deletion of a key upstream regulator Rubicon or other downstream autophagy components, exacerbated disease onset and severity, while deletion of microglial autophagy alone had no measurable effect. Mice presented with robust deposition of the neurotoxic AD protein β-amyloid(Aβ), microglial activation and inflammatory cytokine production, tau phosphorylation, and aggressive neurodegeneration culminating in severe memory impairment. LANDO-deficiency impaired recycling of receptors that recognize Aβ, including TLR4 and TREM2. LANDO-deficiency alone through deletion of the WD-domain of the autophagy protein ATG16 L, revealed a role for LANDO in the spontaneous establishment of age-associated AD. LANDO-deficient mice aged to 2 years presented with advanced ADlike disease and pathology correlative to that observed in human AD patients. Together, these studies illustrate an important role for microglial LANDO in regulating CNS immune activation and protection against neurodegeneration. New evidence is emerging that demonstrates a putative linkage between pathways such as LANDO and cell death regulation via apoptosis and possibly necroptosis. Herein, we provide a review of the use of the autophagy machinery
基金National Science Foundation of China,Grant/Award Numbers:82022010,8201101478,81970613,82000680Beijing Natural Science Foundation,Grant/Award Number:Z190023+2 种基金Fok Ying Tung Education Foundation,Grant/Award Number:171030Beijing Nova Program Interdisciplinary Cooperation Project,Grant/Award Number:Z191100001119004CAMS Innovation Fund for Medical Sciences,Grant/Award Number:2019-I2M-5-046。
文摘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.
