{"doi":"10.1002/ctm2.1200","title":"The microglial immunoreceptor tyrosine‐based motif‐Syk signaling pathway is a promising target of immunotherapy for Alzheimer's disease","abstract":"Alzheimer's disease (AD) is the most common form of dementia in the elderly.1 Age is the greatest risk factor for AD; thus, with the global increasing age of the population, the significance of this health problem will continue to escalate. The pathogenic mechanisms underlying AD are multifactorial and remain incompletely understood. AD can be classified into two subtypes: autosomal dominant AD (ADAD) and sporadic AD. ADAD represents less than 1% of all cases: it is caused by mutations in Amyloid precursor protein (APP), Presenilin 1 (PSEN1), or Presenilin 2 (PSEN2) genes, which control the proteolytic processing of the APP into the amyloid-β (Aβ) peptides.2 Genome-wide association studies have revealed that the genetic risk factors of sporadic AD are more diversified and include, among others, genes controlling microglial activation, such as immune receptors (TREM2, MS4A4A, and CD33), signaling intermediates (PLCG2 and INPP5D) and growth factors (IL34).3 For instance, a partial loss-of-function TREM2 missense variant, R47H, significantly increases AD risk, whereas decreased AD risk is correlated with a gain-of-function P522R variant of PLCG2, a phospholipase Cγ family member that is a downstream signaling effector of TREM2. Therefore, a potential AD therapy based on microglia activation has raised broad attention. Microglia, the brain resident macrophages, respond to Aβ deposition by forming a barrier that attenuates propagation and toxicity of Aβ in the early stage of AD. Transcriptional analysis has demonstrated that during this process microglia convert from homeostatic microglia to disease-associated microglia (DAM) through a transitional state (TM). Moreover, microglia around plaques proliferate. Our previous results revealed that TREM2 deficiency in AD mouse models restricts the ability of microglia to surround Aβ plaques,4 proliferate,5 and convert to DAM.6 These defective microglia response leads to greater neuritic dystrophy adjacent to Aβ plaques. Based on this role in sustaining microglia response to Aβ, TREM2 is currently explored for antibody-mediated immunotherapy.7, 8 However, TREM2 is just one of the receptors that activate microglia through the immunoreceptor tyrosine-based motif (ITAM) signaling pathway, which is mediated by the protein tyrosine kinase SYK. This kinase phosphorylates and activates various downstream effector pathways, such as the PI3K-AKT-mTOR and the PLCγ2-Ca2+ pathways. Conversely, SYK-mediated phosphorylation of GSK3β inactivates GSK3β, releasing β-catenin from inhibition thereby inducing proliferation. In our recent publication in Cell,9 we examined the impact of the SYK pathway on microglia by generating a Syk conditional knockout mouse that selectively lacks SYK in microglia and crossing this mouse with the 5xFAD mouse model of Aβ pathology. We found that constitutive SYK deficiency impaired microglia's ability to respond to Aβ plaques, resulting in increased Aβ accumulation, neurite dystrophy, and memory deficits. Moreover, induction of SYK deletion at a late stage of the disease reversed microglial clustering around Aβ plaques, suggesting that SYK is required not only for a generation but also for the maintenance of microglia responses to Aβ. Microglia express a large network of germline-encoded activating receptors that transmit signals through SYK. Integrins that control adhesion and migration also signal through SYK. Thus, we expected that SYK deficiency would also affect microglial development or homeostasis. However, we observed no obvious defects in microglial numbers, morphology, and phenotype in the absence of Aβ, suggesting that SYK signaling is redundant for microglia development and, self-renewal. Another unexpected observation of our study is that although many ITAM-signaling receptors transmit signals through SYK, the amyloid pathology observed in SYK-deficient mice was not more severe than that observed in TREM2-deficient mice, suggesting that TREM2 is the predominant m","journal":"Clinical and Translational Medicine","year":2023,"id":338043,"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":17,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9644,"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":71132,"name":"Marco Colonna","orcid":"0000-0001-5222-4987","position":1,"is_corresponding":false},{"id":225562,"name":"Shoutang Wang","orcid":"0000-0003-1049-9127","position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":null,"created_at":"2026-07-19T01:10:31.133446Z","pmid":"36772935","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":[]}