Dying by fire: noncanonical functions of autophagy proteins in neuroinflammation and neurodegeneration  

作　　者：Alexis D.Rickman Addison Hilyard Bradlee L.Heckmann 

机构地区：[1]Department of Cell Biology,Microbiology&Molecular Biology University of South Florida,Tampa,FL,USA [2]USF Health Byrd Alzheimer’s Center and Neuroscience Institute,Morsani College of Medicine,Tampa,FL,USA [3]Department of Molecular Medicine,Morsani College of Medicine,Tampa,FL,USA

出　　处：《Neural Regeneration Research》2022年第2期246-250,共5页中国神经再生研究（英文版）

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。

摘　　要：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

关 键 词：aging Alzheimer's disease AUTOPHAGY inflammation LC3-associated endocytosis MICROGLIA NEURODEGENERATION NEUROINFLAMMATION 

分 类 号：R741[医药卫生—神经病学与精神病学]