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. 2019 May 1;11(1):38. doi: 10.1186/s13195-019-0491-2.

Abstract

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 [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 APPswe/PS1dE9 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 APPswe/PS1dE9 mice, compared to age-matched, wild-type animals. The maximal velocity uptake rate (Vmax) 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 Aβ40/42 ratio increased in the aged transgenic brain. At concentrations compatible with those measured in 20-month-old APPswe/PS1dE9 mice, synthetic human Aβ40, but not Aβ42, reduced the baseline Vmax of [3H]5-HT by ~ 20%. Neuroinflammation in APPswe/PS1dE9 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.

Keywords: APP swe /PS1 dE9; Alzheimer’s disease; Amyloid-beta; Cytokines; DASB; Neuroinflammation; SSRIs; Serotonin transporter; TSPO.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / complications
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Disease Models, Animal
  • Encephalitis / complications
  • Encephalitis / metabolism*
  • Female
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neocortex / metabolism*
  • Peptide Fragments / metabolism*
  • Serotonin Plasma Membrane Transport Proteins / metabolism*

Substances

  • Amyloid beta-Peptides
  • Peptide Fragments
  • Serotonin Plasma Membrane Transport Proteins
  • Slc6a4 protein, mouse
  • amyloid beta-protein (1-40)