It is well-established that innate immunity plays a significant role in responding to and influencing the progression of Alzheimer’s disease (AD) (Heneka et al., 2015). Genome-wide association studies (GWAS) have successfully pinpointed several variants in genes expressed in myeloid cells, such as Apoe (Corder et al., 1993; Tang et al., 1996), Trem2 (Jonsson et al., 2013), complement C3b/C4b receptor 1 (Cr1) (Neuner et al., 2020; Novikova et al., 2021; Villegas-Llerena et al., 2016), and Ms4a (Novikova et al., 2021) can increase the risk of developing AD. Through new cutting-edge technologies, including single-cell transcriptomics, proteomics, and epigenetic profiling, the remarkable heterogeneity of microglia has been revealed (Hammond et al., 2019). Indeed, a unique phenotype has been identified as disease-associated microglia (DAM) or neurodegenerative microglia (MGnD), which in AD is enriched with Apoe, Trem2, Lpl, Itgax, Clec7a and Lgals3 (encoding Gal-3) (Keren-Shaul et al., 2017; Krasemann et al., 2017).
Gal-3 has emerged as an essential player in the microglia-mediated innate immune response occurring in the AD brain (Boza-Serrano et al., 2022, 2019). We were the first to report that Gal-3 promotes Αβ toxicity and worsens cognition in an AD mouse model, later confirmed by Tao et al. (Boza-Serrano et al., 2019; Tao et al., 2020). These findings have been followed up clinically in a phase 1b/2a clinical trial conducted by TrueBinding, Inc., in which a monoclonal antibody targeting gal-3 has shown remarkable positive preliminary data in 170 AD patients (NCT05476783). However, how functionality is relevant to Gal-3+ microglia and how these microglia contribute to Aβ pathology across various stages of the disease are unknown.
The aim of the research project is to identify the cell type responsible for interacting with leukocytes, thereby propelling the progression of Aβ pathology. Building upon our preliminary results, we will investigate the role of microglia, prominent innate mediators in the brain, as targets for the orchestration of leukocytes via Gal-3 signalling. We will also evaluate the hypothesis that microglia-release Gal-3 impacts the integrity of BBB through perivascular macrophages and the glymphatic system, ultimately leading to aberrant T-cell response in AD.
Contact: Yiyi Yang, yiyi.yang@med.lu.se