S100 proteins are calcium-binding proteins that regulate several processes connected with Alzheimers disease (AD) but whose contribution and direct involvement in disease pathophysiology remains to be fully established. and relative S100 and A K145 levels. Additionally, S100s are also known to influence AD-related signaling pathways Rabbit Polyclonal to ALS2CR11 and levels of other cytokines. Recent evidence also suggests that metal-ligation by S100 proteins influences trace metal homeostasis in the brain, particularly of zinc, K145 which is also a major deregulated process in AD. Altogether, this evidence strongly suggests a K145 role of S100 proteins as key players in several AD-linked physiopathological processes, which we discuss in this review. cell assays, A42 reduces extracellular release of S100A9 in human THP-1 monocytes (Lee et al., 2013) and induces S100A9 expression in microglia BV2 cells (Ha et al., 2010). However, in CSF from AD patients with mild cognitive impairment and vascular dementia, the levels of S100A9 and A42 are decreased (Horvath et al., 2016). Knockdown of S100A9 decreases cognition decline on Tg2576 mice and reduces amyloid plaque burden (Ha et al., 2010; Chang et al., 2012). K145 S100A9 was found within amyloid plaques of sporadic and familial PS-1 AD brains (Shepherd et al., 2006; Wang et al., 2018) with distinct Braak stages from III to VI (Kummer et al., 2012; Wang C. et al., 2014). Indeed, in some studies it was possible to observe A42 plaques and also isolated S100A9 plaques that are not colocalized, forming separate tissue deposits (Horvath et al., 2016; Wang et al., 2018). Regarding the formation of S100A9 puncta in AD brain, a recent study reported that, biophysical approaches showed that S100A9 binds to A40 through hydrophobic interactions (Zhang et al., 2012; Zhao et al., 2013; Wang C. et al., 2014). Kinetic assays suggested that S100A9 co-aggregates K145 with A40, promoting the formation of amyloid fibrils. The co-aggregation of S100A9 with A42 was also referred to inhibit A42 cytotoxicity (Wang C. et al., 2014). Regarding APP processing, it was found that C-terminal fragments of amyloid precursor-like protein 2 (APLP2) upregulate S100A9 protein and mRNA expression in BV2 cell and that inhibitor of -secretase promotes downregulation of S100A9 protein levels (Li et al., 2014). AD mice deficient in S100A9 have decreased levels of key cytokines involved in APP processing and a reduction of BACE1 expression and activity (Kummer et al., 2012). S100A9 knockout also reduced overall levels of A and APP C-terminal fragments in Tg2576 AD mice, due to increase in neprilysin levels and decreased BACE activity (Chang et al., 2012). Knockdown of S100A9 significantly attenuated the increase of Ca2+ levels provoked by C-terminals of APP or by A treatment (Ha et al., 2010); however, others observed that a reduction of S100A9 extracellular release is followed by an increase in intracellular Ca2+ levels (Lee et al., 2013), evidencing a correlation between calcium and S100A9 dysregulation in AD. In the Advertisement mind and in mouse versions, S100A9 exists in its indigenous type but also as huge complexes which range from 90 to 190 kDa (Shepherd et al., 2006). Certainly, after intranasal administration of S100A9 fibrils in aged mice, S100A9 plaques had been observed in the mind which led to an exacerbation of cell tension (Iashchishyn et al., 2018). Overall there are solid evidences regarding S100A9 as a potential regulator of AD pathways. S100A12 S100A12 is the least studied S100 protein in the context of AD. To date, a single study reported S100A12 hexamers associated with senile plaques, reactive glia and neurons in brains of sporadic and PS-1 AD patients (Shepherd et al., 2006). Outlook Considering the involvement of S100 proteins in multiple regulatory functions in the brain, the fact that they have age- and damage- related expression, and.