Neuroinflammation and amyloid-beta 40 are associated with reduced serotonin transporter (SERT) activity in a transgenic model of familial Alzheimer's disease.

摘要: Discrepant and often contradictory results have accumulated regarding the antidepressant pro-cognitive effects of serotonin transporter (SERT) antagonists in Alzheimer’s disease. To address discrepancy, we measured activity density SERT neocortex 3–24-month-old APPswe/PS1dE9 wild-type littermate mice, by using [3H]DASB autoradiography [3H]5-HT uptake assay. Levels soluble amyloid-β (Aβ), pro-inflammatory cytokines that can regulate function, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor (TNF), were parallel. Neuroinflammation aging mice was further evaluated [3H]PK11195 autoradiography. Decreased observed parietal frontal cortex 18–24-month-old compared to age-matched, animals. The maximal velocity rate (Vmax) reduced neocortical preparations from 20-month-old transgenic vs. mice. reduction when proportion Aβ40 Aβ40/42 ratio increased aged brain. At concentrations compatible with those synthetic human Aβ40, but not Aβ42, baseline Vmax ~ 20%. evidenced elevated binding levels concentration IL-1β protein, which preceded reductions activity. Age-induced increases IL-1β, IL-6, TNF both progression cerebral amyloidosis is associated neuroinflammation decreased presynaptic markers serotonergic integrity Aβ40-induced kinetics suggests SERT, potentially antagonism, depend on interstitial Aβ40.