Alzheimer’s disease (AD), one of the most common forms of dementia, constitutes a high social and economic burden expected to increase in the upcoming years [1]. AD pathology presents a complex etiology influenced by genetic and environmental factors. The genetic expression of APOE4 constitutes one of the highest genetic risk factors for developing AD, yet, new mutations are being discovered potentially influencing AD’s pathology, hence evidencing the profound impact of the APOE genotype in AD pathophysiology [2]. Multiple studies have revealed that early-life exposure to environmental factors, pollutants or infectious agents impact AD development [3]. Astrocytes are the main producers of apoE; However, microglia can also act as an apoE source under chronic inflammatory conditions or during aging [4-6]. Nonetheless, the precise mechanisms through which APOE4 exerts its deleterious effects are yet to be determined.
Aside from AD’s main pathological hallmarks, chronic neuroinflammation strongly contributes to AD pathogenesis [7]. Microglia and astrocytes are the primary mediators of neuroinflammation, and multiple efforts have been directed at finding effective biomarkers of AD-related neuroinflammation and the molecular mechanisms intertwined. Thus, finding factors limiting neuroinflammation would be greatly useful as therapeutic agents.
APOE4 aggravates amyloid pathology, increases microglial reactivity, and worsens cognition in animal models of AD [8, 9]. ApoE interacts with multiple ligands, among them triggering-receptor expressed on myeloid cells 2 (TREM2), which is greatly implicated in neuroinflammation [5]. Interestingly, our group found that galectin 3 (Gal3) is a crucial modulator of AD-related neuroinflammation, which, as well as apoE, communicates through TREM2 [10]. Recent findings have highlighted an increase of the Gal3 gene (lgal3) in apoE4-microglia and upregulated APOE levels, particularly in aged microglia [6]. Moreover, our group has recently evidenced that early-life infection in 5xFAD mice induces a subpopulation of microglial cells with a monocyte-like profile presenting as potential markers genes corresponding to Gal3, and APOE. Since Galectin-3 is a relevant mediator of neuroinflammation, determining the impact of Gal3 in the glial response during AD in the context of APOE4 would be of great interest. Hence, characterizing the microglial signature and unraveling the molecular mechanisms implicated in the detrimental effects of brain-derived apoE4 is crucial for developing efficient therapies for AD.
Contact: Rosalia Fernandez-Calle, rosalia.fernandez_calle@med.lu.se
References
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