A role for sodium glucose cotransporter 2 inhibitors (SGLT2is) in the treatment of Alzheimer's disease?

Abstract

With the lack of success and increasing urgency for therapies capable of impacting Alzheimer's disease (AD) and its progression, there are increasing efforts to expand testing of new mechanistic hypotheses to attack the disease from different angles. Three such hypotheses are the "Mitochondrial Cascade (MC)" hypothesis, the "Endo-Lysosomal Dysfunction (ELD)" hypothesis and the "Type 3 Diabetes (T3D)" hypothesis. These hypotheses provide a rationale for new pharmacological approaches to address the mitochondrial, endo-lysosomal and metabolic dysfunction associated with AD. It is increasingly evident that there is critical interplay between the metabolic dysfunction associated with obesity/metabolic syndrome/type 2 diabetes mellitus (T2DM) and patient susceptibility to AD development. A candidate for a common mechanism linking these metabolically-driven disease states is chronically-activated mechanistic target of rapamycin (mTOR) signaling. Unrestrained chronic mTOR activation may be responsible for sustaining metabolic, lysosomal and mitochondrial dysfunction in AD, driving both the breakdown of the blood-brain barrier via endothelial cell dysfunction and hyperphosphorylation of tau and formation of amyloid plaques in the brain. It is hypothesized that sodium glucose cotransporter 2 (SGLT2) inhibition, mediated by sustained glucose loss, restores mTOR cycling through nutrient-driven, nightly periods of transient mTOR inhibition (and restoration of catabolic cellular housekeeping processes) interspersed by daily periods of transient mTOR activation (and anabolism) accompanying eating. In this way, a flexible mTOR dynamic is restored, thereby preventing or even reducing the progress of AD pathology. The first study to investigate the effect of SGLT2 inhibition in patients with AD is ongoing and focuses on the impact on energy metabolism in the brain following treatment with the SGLT2 inhibitor dapagliflozin.

Keywords: AMPK; Alzheimer's disease; Autophagy; Circadian; Fasting; Gluconeogenesis; Glycogen; Ketones; Lysosome; Mitochondria; Proteostasis; SGLT2 inhibition; Type 2 diabetes; ULK1; mTOR.