FIGURE 1.

Simplified schematic illustrating putative pleiotropic effects of ketotherapies as modulators of amyloid-β. Ketotherapies (KTs) potentially modulate amyloid-β (Aβ) through various direct and indirect mechanisms targeting poor mitochondrial bioenergetics, increased ROS, and increased inflammation. KTs, especially the ketogenic diet (KD), reduce systemic insulin and potentially improve peripheral metabolic status which may improve systemic inflammation and reduce Aβ. The ketone body, β-hydroxybutyrate (BHB), serves as an energy substrate for mitochondrial metabolism, upregulates the astrocyte-neuron lactate shuttle, activates hydrocarboxylic acid receptor 2 (HCA2) to regulate inflammation, and may directly scavenge reactive oxygen species (ROS). Through bioenergetic effects in the mitochondria, KTs stimulate genesis of new mitochondria, increase uncoupling of the electron transport chain (ETC) to increase ATP production, generate less ROS than glucose metabolism, and reduce mitochondrial import of amyloid precursor protein (APP) and Aβ. KTs also activate nuclear factor-E2 related factor 2 (Nrf2) to upregulate synthesis of ROS-scavenging antioxidants and AMP-activated protein kinase (AMPK) to regulate transcription of pro-inflammatory cytokines. This figure created with BioRender (https://biorender.com).