Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Abstract

Aggregation of amyloid-β (Aβ) as toxic oligomers and amyloid plaques within the brain appears to be the pathogenic event that initiates Alzheimer's disease (AD) lesions. One therapeutic strategy has been to reduce Aβ levels to limit its accumulation. Activation of certain neurotransmitter receptors can regulate Aβ metabolism. We assessed the ability of serotonin signaling to alter brain Aβ levels and plaques in a mouse model of AD and in humans. In mice, brain interstitial fluid (ISF) Aβ levels were decreased by 25% following administration of several selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Similarly, direct infusion of serotonin into the hippocampus reduced ISF Aβ levels. Serotonindependent reductions in Aβ were reversed if mice were pretreated with inhibitors of the extracellular regulated kinase (ERK) signaling cascade. Chronic treatment with an SSRI, citalopram, caused a 50% reduction in brain plaque load in mice. To test whether serotonin signaling could impact Aβ plaques in humans, we retrospectively compared brain amyloid load in cognitively normal elderly participants who were exposed to antidepressant drugs within the past 5 y to participants who were not. Antidepressant-treated participants had significantly less amyloid load as quantified by positron emission tomography (PET) imaging with Pittsburgh Compound B (PIB). Cumulative time of antidepressant use within the 5-y period preceding the scan correlated with less plaque load. These data suggest that serotonin signaling was associated with less Aβ accumulation in cognitively normal individuals.microdialysis | selective serotonin reuptake inhibitor antidepressants | late-life depression A myloid-β (Aβ) dysregulation appears to initiate the pathogenesis of Alzheimer's disease (AD) with a cascade of downstream factors that exacerbate and propagate neuronal injury (1). Aβ can accumulate as toxic plaques and soluble oligomers in the brains of individuals with AD a decade or more before the initial symptoms are identified (2). The concentration of Aβ is a critical factor determining if and when it will aggregate into these toxic structures; high concentrations of Aβ are more prone to convert from its normal soluble form into these multimeric conformations (3). Aβ is formed within neurons by sequential cleavage of the amyloid precursor protein (APP) by two enzymes, β-secretase and then γ-secretase. Alternatively, α-secretase can cleave APP within the Aβ sequence, which precludes the peptide from being formed at all. The enzymes and mechanisms that produce Aβ have been well characterized; however, the mechanisms that regulate Aβ production and levels are only partly understood. Understanding the cellular processes that regulate Aβ levels may provide greater insight into disease pathogenesis and suggest new avenues to treat or prevent AD.Synaptic activity is one key regulator of brain Aβ production. Depolarization and subsequent synaptic transmission causes Aβ to be produced presynaptically and then secreted into the brain extracel...

Neurochemicals, Behaviours and Psychiatric Perspectives of Neurological Diseases

“…Moreover, production of toxic Aβ proteins and plaques decreased upon administration of selective serotonin reuptake inhibitors (SSRIs) in AD mouse models. Similar results were obtained upon infusion of serotonin into the hippocampus of AD mice [184]. In humans, lower cortical amyloid levels were observed in participants who had been administered SSRIs in the past five years [186].…”

“…Similarly, 5-HT1B/1D was also found to be associated with cognitive dysfunction in AD. A recent study confirmed that 5-HT1B/1D receptor density was significantly reduced in the frontal and temporal cortex of AD patients with impaired Mini-Mental State Examination (MMSE) scores [184].…”

“…Interestingly, reduced serotonin levels and increased 5-HT1A receptor density in the neo cortex are associated with cognitive impairment in AD. Whereas, the expression of 5-HT(6) and 5-HT(1B/1D) receptors are found to be reduced in the frontal and temporal cortex of the AD patients with low Mini-Mental State Examination (MMSE) scores [184]. In the hippocampus, a negative correlation exists between the activity of 5-HT1A receptors and verbal memory.…”

“…Cognitive impairments observed in AD are known to be associated with increased 5-HT1A receptor density. Cirrito et al [184] demonstrated that activation of serotonergic neurotransmission is beneficial in AD. Moreover, production of toxic Aβ proteins and plaques decreased upon administration of selective serotonin reuptake inhibitors (SSRIs) in AD mouse models.…”

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

“…Stimulation of 5-hydroxytryptamine receptors was shown to promote nonamyloidogenic processing of APP [76][77][78][79], and the SSRIs paroxetine and imipramine reduced Aβ levels in mouse models of AD [80]. Direct analysis of brain interstitial fluid using microdialysis revealed that citalopram, desvenlafaxine, and fluoxetine reduced the interstitial fluid Aβ levels in presenilin 1 APP double transgenic mice [81]. Chronic administration of citalopram also substantially reduced Aβ plaque burden.…”