Revisiting Alzheimer's Disease Through the Somatostatin-Mitochondria Axis.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and pathological hallmarks such as amyloid-beta (Aβ) deposition and tau hyperphosphorylation. Increasing evidence identifies mitochondrial dysfunction as an early and central driver of AD pathogenesis, contributing to impaired bioenergetics, oxidative stress, disrupted calcium homeostasis, and synaptic failure. Notably, somatostatin (SST), a neuropeptide significantly reduced in AD brains, has emerged as a candidate regulator of neuronal metabolism and mitochondrial homeostasis. In this review, we propose a conceptual and testable framework linking reduced SST signaling to mitochondrial dysfunction in AD. Current evidence most directly supports effects of SST signaling on neuronal excitability and calcium homeostasis, whereas direct evidence linking SST or individual SSTR subtypes-particularly SSTR2 and SSTR4-to mitochondrial bioenergetics, mitophagy, cristae organization, and mitochondrial dynamics remains limited and is discussed here largely at the level of plausible, testable hypotheses. Downstream signaling pathways, including Gi-coupled inhibition of cAMP/PKA and modulation of PI3K/Akt, have established roles in neuronal signaling and are discussed here in relation to their potential, but not yet directly demonstrated, contributions to mitochondrial bioenergetics, redox balance, calcium handling, mitophagy, and mitochondrial dynamics. Disruption of these processes may plausibly contribute to a self-amplifying cycle involving Aβ accumulation, tau pathology, and synaptic dysfunction, although this cycle has not been directly demonstrated for SST signaling specifically. Collectively, the SST-mitochondria axis represents a conceptual and testable framework that may help explain aspects of AD pathogenesis, pending direct mechanistic validation, offering promising therapeutic opportunities beyond conventional amyloid- and tau-centric approaches. Future research should focus on receptor subtype-specific mechanisms, mitophagy modulation, and mitochondrial calcium regulation to advance translational applications.