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

BACKGROUND:Discrepant and often contradictory results have accumulated regarding the antidepressant and pro-cognitive effects of serotonin transporter (SERT) antagonists in Alzheimer's disease. METHODS:To address the discrepancy, we measured the activity and density of SERT in the neocortex of 3-24-month-old APP_swe/PS1_dE9 and wild-type littermate mice, by using [³H]DASB autoradiography and the [³H]5-HT uptake assay. Levels of soluble amyloid-β (Aβ), and pro-inflammatory cytokines that can regulate SERT function, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor (TNF), were measured in parallel. Neuroinflammation in aging APP_swe/PS1_dE9 mice was further evaluated by [³H]PK11195 autoradiography. RESULTS:Decreased SERT density was observed in the parietal and frontal cortex of 18-24-month-old APP_swe/PS1_dE9 mice, compared to age-matched, wild-type animals. The maximal velocity uptake rate (V_max) of [³H]5-HT was reduced in neocortical preparations from 20-month-old transgenic vs. wild-type mice. The reduction was observed when the proportion of soluble Aβ₄₀ in the Aβ_40/42 ratio increased in the aged transgenic brain. At concentrations compatible with those measured in 20-month-old APP_swe/PS1_dE9 mice, synthetic human Aβ₄₀, but not Aβ₄₂, reduced the baseline V_max of [³H]5-HT by ~ 20%. Neuroinflammation in APP_swe/PS1_dE9 vs. wild-type mice was evidenced by elevated [³H]PK11195 binding levels and increased concentration of IL-1β protein, which preceded the reductions in neocortical SERT density and activity. Age-induced increases in the levels of IL-1β, IL-6, and TNF were observed in both transgenic and wild-type animals. CONCLUSIONS:The progression of cerebral amyloidosis is associated with neuroinflammation and decreased presynaptic markers of serotonergic integrity and activity. The Aβ₄₀-induced reduction in the uptake kinetics of [³H]5-HT suggests that the activity of SERT, and potentially the effects of SERT antagonism, depend on the levels of interstitial Aβ₄₀.

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