Figure 6.

Schematic model of sequential hippocampal aging changes. EARLY ADULT, Early age-related alterations in hippocampal gene expression suggest an aging-related metabolic shift from glucose to FFAs/AAs/KBs as predominant fuel source. This shift appears orchestrated primarily in astrocytes with upregulation of genes in pathways for lipid and protein catabolism and upregulation of the lysosomal pathway. INTERMEDIATE, Astrocytes generate increased FFAs and AAs by releasing cytokines and complement components that trigger microglial inflammatory degradation of the lipid- and protein-rich myelin sheath, generating excess cholesterol as a byproduct. MIDLIFE/LATE, Increased excess cholesterol triggers upregulation of astrocytic ApoE, cholesterol trafficking, and myelinogenic programs that enable incorporation of excess cholesterol from ApoE-containing lipoproteins into remyelinating oligodendrocytes for storage/disposal. Elevated proteolysis activates antigen-presenting pathways in microglia. Together, the increased inflammation and energy-expensive glial activation induce damage in neurons (dashed outline) and compete for energy with neuronal signaling pathways, resulting in cognitive impairment.