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

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 APP swe /PS1 dE9 and wild-type littermate mice, by using [ 3 H]DASB autoradiography and the [ 3 H]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 [ 3 H]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 [ 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 Aβ 40 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 Aβ 40 , but not Aβ 42 , reduced the baseline V max of [ 3 H]5-HT by ~ 20%. Neuroinflammation in APP swe /PS1 dE9 vs. wild-type mice was evidenced by elevated [ 3 H]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 Aβ 40 -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 Aβ 40 .

Dopamine beta‐hydroxylase and its genetic variants in human health and disease

“…Severe deficits in the cholinergic system have been linked to AD, and cholinergic neurons in the nucleus basalis of Meynert have been identified as a progression marker of cognitive decline in AD (Whitehouse et al ; Whitehouse et al ). Other neurotransmitter systems, including NE, serotonin, glutamate, and somatostatin, are believed to contribute to the disease (Esposito et al ; Solarski et al ; Park et al ; Quevenco et al ; Metaxas et al ). Currently, no effective therapeutics are available to either halt or reverse the progression of AD that is likely because of its polygenic nature (Gold ).…”

Highlighting Immune System and Stress in Major Depressive Disorder, Parkinson’s, and Alzheimer’s Diseases, with a Connection with Serotonin

“…Thus, these data demonstrate that, during AD, these cytokines interfere with the serotonergic system in specific ways for each cytokine, with the need for studies in this area [118]. However, it is important to keep in mind that the research about this topic highlights that the progression of cerebellar amyloidosis, a characteristic of AD, is associated with neuroinflammation, which is mirrored in events such as changes in integrity and pre-synaptic serotonergic activity [116]. Another study linked AD, depression, and the immune system.…”

“…Thus, a connection between serotonin, neuroinflammation, and AD is evident [114,115]. Studies have shown that changes in the function of the serotonin transporter are caused by proinflammatory cytokines elevated in AD, such as interleukin-1 beta [116]. Also, in studies with neuronal cell lines and in vivo studies, TNF has been shown to increase the maximum uptake rate of serotonin [117].…”

Is the Exposome Involved in Brain Disorders through the Serotoninergic System?

“…It was demonstrated that knocking out the gene of this molecule in mice models of AD improved the animals' performance in both learning and memory tests, despite them having more plaques in their brains and fewer activated microglia [158]. Increased proinflammatory cytokines in AD, such as IL-1β and TNFα, impact the serotoninergic system by increasing the uptake rate of serotonin [159] through SERT [160]. Therefore, such an effect could lead to decreased serotonin levels, which might be related to depression that is currently observed in AD patients.…”