Somatostatin and the pathophysiology of Alzheimer's disease

Ageing Res Rev. 2024 Mar 12:102270. doi: 10.1016/j.arr.2024.102270. Online ahead of print.ABSTRACTAmong the central features of Alzheimer's disease (AD) progression are altered levels of the neuropeptide somatostatin (SST), and the colocalisation of SST-positive interneurons (SST-INs) with amyloid-β plaques, leading to cell death. In this theoretical review, I propose a molecular model for the pathogenesis of AD based on SST-IN hypofunction and hyperactivity. Namely, hypofunctional and hyperactive SST-INs struggle to control hyperactivity in mid-temporal regions in early stages, leading to axonal Aβ production through excessive presynaptic GABAB inhibition, GABA-B1a/APP complex downregulation and internalisation. Concomitantly, excessive SST-14 release accumulates near SST-INs in the form of amyloids, which bind to Aβ to form toxic mixed oligomers. This leads to differential SST-IN death through excitotoxicity, further disinhibition, SST deficits, and increased Aβ release, fibrillation and plaque formation. Aβ plaques, hyperactive networks and SST-IN distributions thereby tightly overlap in the brain. Conversely, chronic stimulation of SST2/4 by SST-INs promotes intense MAPK p38 activity, leading to p-tau staining and apoptosis/neurodegeneration, in agreement with a near complete overlap between p38 and tangles. Finally, the molecular model is shown capable of shedding light on qualitative aspects of AD neuropsychology, especially within the domains of spatial and declar...
Source: Ageing Research Reviews - Category: Genetics & Stem Cells Authors: Source Type: research