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[221021 Àú³Î¹ßÇ¥] SYK coordinates neuroprotective microglial responses in neurodegenerative disease

À̵¿ÁØ ¦¢ 2022-10-20

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2022 Oct 6;S0092-8674(22)01249-1.
 doi: 10.1016/j.cell.2022.09.030. Online ahead of print.

SYK coordinates neuroprotective microglial responses in neurodegenerative disease

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Abstract

Recent studies have begun to reveal critical roles for the brain's professional phagocytes, microglia, and their receptors in the control of neurotoxic amyloid beta (A¥â) and myelin debris accumulation in neurodegenerative disease. However, the critical intracellular molecules that orchestrate neuroprotective functions of microglia remain poorly understood. In our studies, we find that targeted deletion of SYK in microglia leads to exacerbated A¥â deposition, aggravated neuropathology, and cognitive defects in the 5xFAD mouse model of Alzheimer's disease (AD). Disruption of SYK signaling in this AD model was further shown to impede the development of disease-associated microglia (DAM), alter AKT/GSK3¥â-signaling, and restrict A¥â phagocytosis by microglia. Conversely, receptor-mediated activation of SYK limits A¥â load. We also found that SYK critically regulates microglial phagocytosis and DAM acquisition in demyelinating disease. Collectively, these results broaden our understanding of the key innate immune signaling molecules that instruct beneficial microglial functions in response to neurotoxic material.

Keywords: Alzheimer¡¯s disease; SYK; amyloid beta; disease-associated microglia; experimental autoimmune encephalomyelitis; microglia; multiple sclerosis; neurodegenerative disease; neuroimmunology; phagocytosis.




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