| First Author | Metaxas A | Year | 2019 |
| Journal | Alzheimers Res Ther | Volume | 11 |
| Issue | 1 | Pages | 38 |
| PubMed ID | 31043179 | Mgi Jnum | J:289207 |
| Mgi Id | MGI:6434668 | Doi | 10.1186/s13195-019-0491-2 |
| Citation | Metaxas A, et al. (2019) Neuroinflammation and amyloid-beta 40 are associated with reduced serotonin transporter (SERT) activity in a transgenic model of familial Alzheimer's disease. Alzheimers Res Ther 11(1):38 |
| abstractText | 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 APPswe/PS1dE9 and wild-type littermate mice, by using [(3)H]DASB autoradiography and the [(3)H]5-HT uptake assay. Levels of soluble amyloid-beta (Abeta), and pro-inflammatory cytokines that can regulate SERT function, such as interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor (TNF), were measured in parallel. Neuroinflammation in aging APPswe/PS1dE9 mice was further evaluated by [(3)H]PK11195 autoradiography. RESULTS: Decreased SERT density was observed in the parietal and frontal cortex of 18-24-month-old APPswe/PS1dE9 mice, compared to age-matched, wild-type animals. The maximal velocity uptake rate (Vmax) of [(3)H]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 Abeta40 in the Abeta40/42 ratio increased in the aged transgenic brain. At concentrations compatible with those measured in 20-month-old APPswe/PS1dE9 mice, synthetic human Abeta40, but not Abeta42, reduced the baseline Vmax of [(3)H]5-HT by ~ 20%. Neuroinflammation in APPswe/PS1dE9 vs. wild-type mice was evidenced by elevated [(3)H]PK11195 binding levels and increased concentration of IL-1beta protein, which preceded the reductions in neocortical SERT density and activity. Age-induced increases in the levels of IL-1beta, 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 Abeta40-induced reduction in the uptake kinetics of [(3)H]5-HT suggests that the activity of SERT, and potentially the effects of SERT antagonism, depend on the levels of interstitial Abeta40. |
