LC3-associated endocytosis: guarding against neuroinflammation & neurodegeneration

DATE: November 19, 2019
TIME: 10:00am PST

Microglial cells are the resident innate immune cells of the central nervous system (CNS) and are responsible for regulating inflammatory activation in response to both physiological and pathological immune perturbations. The mechanisms that fully control and dictate the nature of an inflammatory response in the CNS are still poorly understood. We have recently identified a novel pathway where components of the canonical autophagy machinery function to conjugate the microtubule-associated protein LC3 to endosomal membranes, a process we have termed LC3-associated endocytosis (LANDO). We further identified that abrogation of LANDO in microglial cells promotes pro-inflammatory cytokine production in vitro. To characterize LANDO and its role in immune regulation in the CNS, we utilized a well-established model of neuroinflammation induced by β-amyloid deposition. We found that mice lacking LANDO but not canonical autophagy in either the myeloid compartment or specifically in microglia, have a robust increase in pro-inflammatory cytokine production in the hippocampus and have increased levels of neurotoxic β-amyloid accumulation. This inflammation and β-amyloid deposition led to reactive microgliosis and hyperphosphorylation of tau, a protein that is vital to neuronal structure and function. As a consequence, LANDO-deficient Alzheimer’s Disease mice have increased neurodegeneration, resulting in impaired neuronal signaling and consequential behavioral and memory deficits. Mechanistically, β-amyloid is internalized by microglial cells through receptor-mediated endocytosis using a variety of surface receptors including Trem2 and CD36. We further identified that LANDO-deficiency not only alters immune activation upon endocytosis of β-amyloid, but results in impaired receptor recycling and extracellular β-amyloid accumulation. Exacerbation of β-amyloid accumulation further contributes to increased neuroinflammation. Together, our data support a protective role for LANDO in microglial cells of the CNS in neurodegenerative pathologies resulting from amyloid deposition.

Learning Objectives:

• Explain the regulation of neuroimmune functions of microglia and the role of the autophagy proteins in governing this process.
• Elucidate novel therapeutic strategies and targets for neurodegenerative diseases including Alzheimer’s Disease.

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