{"doi":"10.1002/ctm2.1178","title":"Microglia rely on SYK signalling to mount neuroprotective responses in models of Alzheimer's disease and multiple sclerosis","abstract":"After a generation of failed therapies, microglia have captivated scientists searching for unexplored avenues to treat neurodegenerative diseases. The last decade of research has unveiled a remarkable capacity for microglia to alter the trajectory of neurodegeneration through the interaction of these brain-resident immune cells with disease pathology and other disease-associated cell types in the brain. Emerging from this collective work is the idea that microglia can play both neuroprotective and deleterious roles in neurological disease pathogenesis. However, what accounts for the acquisition of damaging versus beneficial functions by microglia is still a matter of great debate in the field. Despite this, recent advances have begun to uncover some of the major transcriptional networks and effector mechanisms that underpin the ability of microglia to impact neurodegenerative disease susceptibility and progression. Unearthing the processes by which microglia can modify pathology in neurodegenerative diseases such as Alzheimer's disease (AD) and multiple sclerosis (MS) will likely hold key therapeutic insights for successful interventions by clinicians. Although numerous mechanisms have been proposed to date, it has become increasingly clear that the ability of microglia to corral and phagocytose neurotoxic material, including amyloid beta (Aβ) in AD and damaged myelin in MS, is essential for them to exert their neuroprotective effects in degenerative disease.1 Consistent with this idea, recent studies demonstrate that the TREM2 receptor is deployed by microglia to coordinate both the containment and phagocytosis of Aβ and dead cells in an effort to limit the toxicity of these pathologies to surrounding neurons.2, 3 The CD33 receptor, on the other hand, has been shown to inhibit the ability of microglia to phagocytose Aβ.4 In-line with this, gain-of-function mutations in CD33 have been strongly linked with AD risk in humans.5 Age is the greatest risk factor for AD, and it has also been proposed that aging-related defects in phagocytosis contribute to the increased risk of developing neurodegenerative disease. This has motivated many groups to perform screens in the search of the molecular players that underlie age-associated decline in microglial phagocytosis. In one such study, it was shown that the receptor CD22 hinders microglial phagocytic capacity during aging.6 Furthermore, relevant to both AD and MS, this study reported that antibody-based blockade of CD22 provides an effective strategy to boost the phagocytosis of both Aβ and myelin debris. Although great strides have recently been made in defining some of the surface receptors that modulate microglial biology in neurodegenerative disease, the identity of the key intracellular signalling molecules exploited by microglia to regulate their neuroprotective functions is currently less well understood. Tremendous efforts in recent years have also been paid to defining how microglial responses evolve during the course of neurodegenerative disease in hopes of unearthing key transcriptional signatures and molecular players that influence disease progression. Emerging from these collective studies is the notion that microglia take on a neuroprotective disease-associated microglia (DAM) phenotype during neurodegenerative disease progression, and that this transformation is meant to equip them with the machinery needed to properly contain and dispose of neurotoxic material.7 This transition is characterized by the downregulation of homeostatic genes such as Tmem119 and P2ry12, and the concomitant upregulation of DAM and neurodegenerative microglia (MGnD) factors that include Lpl, Ccl6, Clec7a, and Cst7.7, 8 Although this paradigm of microglial activation has been extensively studied and adopted in multiple models of neurological disease, we currently lack knowledge of the key signalling molecules that instruct this important transformation in microglia. However, in our recent work","journal":"Clinical and Translational Medicine","year":2023,"id":333013,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":23,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9502,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":232068,"name":"John R. Lukens","orcid":"0000-0002-6795-0866","position":1,"is_corresponding":false},{"id":232064,"name":"Hannah Ennerfelt","orcid":"0000-0003-4861-0740","position":0,"is_corresponding":true}],"reference_count":11,"raw_metadata":null,"created_at":"2026-07-19T01:09:35.125543Z","pmid":"36629045","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}