Abstract
Accumulation of β-amyloid (Aβ) and resultant inflammation are critical pathological features of Alzheimer disease (AD). Microglia, a primary immune cell in brain, ingests and degrades extracellular Aβ fibrils via the lysosomal system. Autophagy is a catabolic process that degrades native cellular components, however, the role of autophagy in Aβ degradation by microglia and its effects on AD are unknown. Here we demonstrate a novel role for autophagy in the clearance of extracellular Aβ fibrils by microglia and in the regulation of the Aβ-induced NLRP3 (NLR family, pyrin domain containing 3) inflammasome using microglia specific atg7 knockout mice and cell cultures. We found in microglial cultures that Aβ interacts with MAP1LC3B-II via OPTN/optineurin and is degraded by an autophagic process mediated by the PRKAA1 pathway. We anticipate that enhancing microglial autophagy may be a promising new therapeutic strategy for AD.
Keywords:
Alzheimer disease; NLRP3; autophagy; microglia; β-amyloid.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
AMP-Activated Protein Kinases / metabolism
-
Adaptor Proteins, Signal Transducing / metabolism
-
Aged
-
Aged, 80 and over
-
Alzheimer Disease / metabolism
-
Alzheimer Disease / pathology
-
Amyloid beta-Peptides / metabolism*
-
Animals
-
Autophagy*
-
Autophagy-Related Protein 7
-
Carrier Proteins / metabolism*
-
Cell Cycle Proteins
-
Cell Line
-
Extracellular Space / metabolism*
-
Eye Proteins / metabolism
-
Female
-
Heat-Shock Proteins / metabolism
-
Humans
-
Inflammasomes / metabolism*
-
Inflammation / pathology
-
Integrases / metabolism
-
Male
-
Membrane Transport Proteins
-
Mice
-
Microglia / metabolism*
-
Microglia / pathology*
-
Microtubule-Associated Proteins / metabolism
-
Models, Biological
-
NLR Family, Pyrin Domain-Containing 3 Protein
-
Neurons / pathology
-
Proteolysis
-
Sequestosome-1 Protein
-
Transcription Factor TFIIIA / metabolism
Substances
-
Adaptor Proteins, Signal Transducing
-
Amyloid beta-Peptides
-
Atg7 protein, mouse
-
Carrier Proteins
-
Cell Cycle Proteins
-
Eye Proteins
-
Heat-Shock Proteins
-
Inflammasomes
-
Membrane Transport Proteins
-
Microtubule-Associated Proteins
-
NLR Family, Pyrin Domain-Containing 3 Protein
-
Nlrp3 protein, mouse
-
OPTN protein, human
-
Optn protein, mouse
-
SQSTM1 protein, human
-
Sequestosome-1 Protein
-
Sqstm1 protein, mouse
-
Transcription Factor TFIIIA
-
AMP-Activated Protein Kinases
-
Cre recombinase
-
Integrases
-
Autophagy-Related Protein 7