Fig. 3

Schematic overview of most pronounced cellular and molecular changes in resilient individuals compared to AD patients. Compared to AD patients, multiple studies have indicated a different glial reaction to AD pathology in resilient donors. A reduction in the total number of microglia based on the markers TREM2, HLA-DR or CD86 have been found in resilient donors, while others have shown an increase of these markers near plaques in resilient donors, indicating a more phagocytotic subpopulation of microglia. While it has been hypothesized that microglia lack a DAM-like phenotype in resilience, this remains to be substantiated. In astrocytes, more homeostatic properties have been found, such as increased processes, increased expression of GLT-1 and reduced amounts of GFAP. Furthermore, an altered cytokine profile was observed in resilient donors. Reductions of both oxidative stress and DNA damage was observed based on the markers PINK, IDH1 and YH2AX. Mitochondria dysfunction was reduced in resilient donors, as increased oxidative phosphorylation and mitochondrial subunits were increased compared to AD patients. Increased levels of the “do not eat me signal” CD47 and increased levels and altered morphologies of dendritic spines were found in resilient donors compared to AD. Abbreviations: CD47; cluster of differentiation 47, DAM; damage associated microglia, CD68; cluster of differentiation 68, GLT-1; glutamate transporter-1, GFAP; glial fibrillary acidic protein, HLA-DR; major histocompatibility complex, class II, DR alpha, IDH1; isocitrate dehydrogenase (NADP( +)) 1, NDUFs; NADH:ubiquinone oxidoreductase core subunits, PINK; PTEN-induced kinase 1, TYROBP; TYRO protein tyrosine kinase-binding protein, YH2AX; H2A histone family member X