Fluoxetine and Vortioxetine Reverse Depressive-Like Phenotype and Memory Deficits Induced by Aβ1-42 Oligomers in Mice: A Key Role of Transforming Growth Factor-β1

Abstract

Depression is a risk factor for the development of Alzheimer’s disease (AD), and the presence of depressive symptoms significantly increases the conversion of mild cognitive impairment (MCI) into AD. A long-term treatment with antidepressants reduces the risk to develop AD, and different second-generation antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are currently being studied for their neuroprotective properties in AD. In the present work, the SSRI fluoxetine and the new multimodal antidepressant vortioxetine were tested for their ability to prevent memory deficits and depressive-like phenotype induced by intracerebroventricular injection of amyloid-β (1-42) (Aβ 1-42 ) oligomers in 2-month-old C57BL/6 mice. Starting from 7 days before Aβ injection, fluoxetine (10 mg/kg) and vortioxetine (5 and 10 mg/kg) were intraperitoneally injected daily for 24 days. Chronic treatment with fluoxetine and vortioxetine (both at the dose of 10 mg/kg) was able to rescue the loss of memory assessed 14 days after Aβ injection by the passive avoidance task and the object recognition test. Both antidepressants reversed the increase in immobility time detected 19 days after Aβ injection by forced swim test. Vortioxetine exerted significant antidepressant effects also at the dose of 5 mg/kg. A significant deficit of transforming growth factor-β1 (TGF-β1), paralleling memory deficits and depressive-like phenotype, was found in the hippocampus of Aβ-injected mice in combination with a significant reduction of the synaptic proteins synaptophysin and PSD-95. Fluoxetine and vortioxetine completely rescued hippocampal TGF-β1 levels in Aβ-injected mice as well as synaptophysin and PSD-95 levels. This is the first evidence that a chronic treatment with fluoxetine or vortioxetine can prevent both cognitive deficits and depressive-like phenotype in a non-transgenic animal model of AD with a key contribution of TGF-β1.

Modulation of Pro-Oxidant and Pro-Inflammatory Activities of M1 Macrophages by the Natural Dipeptide Carnosine

“…It has been shown in vivo that the administration of TGF-β1 is able to protect against Aβ-induced neuroinflammation and neurodegeneration [84][85][86], whilst mutations of the TGF-β1 gene in mice lead to death from multifocal inflammation and autoimmune disorders in internal organs [87,88]. Additionally, a significant deficit of TGF-β1, paralleling memory deficits and depressive-like phenotype, has been found in the hippocampus of Aβ-injected mice [89]. Very recently, the ability of carnosine to protect brain macrophages and neurons against Aβ-induced cell toxicity by increasing TGF-β1 expression and secretion has been proposed [23].…”

Antidepressant Drugs and Physical Activity: A Possible Synergism in the Treatment of Major Depression?

“…Stress exposure also leads to an impairment of TGF-β1 signaling in different brain regions (hippocampus, cortex, and hypothalamus) (You et al, 2011;Caraci et al, 2015). This impairment has been connected to the onset of a depressive-like phenotype in mice (Torrisi et al, 2019). Lastly, a correlation between reduced TGF-β1 plasma levels, depression severity, and treatment resistance in MDD has been proved (Sutcigil et al, 2007;Caraci et al, 2018a).…”

“…Likewise, a decrease of TGF-β1 levels has been observed in hippocampus and cortex of animal models of depression (Yu et al, 2011); furthermore, several studies carried out in depressed patients have demonstrated that plasma TGF-β1 levels are reduced and correlate with depression severity (Myint et al, 2005;Rush et al, 2016). A chronic treatment with first-and second-generation antidepressants rescues BDNF levels in different preclinical models of depression (Duman and Monteggia, 2006), while selective serotonin reuptake inhibitors (SSRIs) drugs and the new multimodal antidepressant vortioxetine are able to reverse the depressive-like phenotype and memory deficits induced by amyloid-β (Aβ) in mice by the rescue of TGF-β1 1 https://www.who.int/health-topics/depression#tab=tab_1 (Torrisi et al, 2019). Furthermore, antidepressant drugs exert immunoregulatory effects reducing the production of proinflammatory cytokines and stimulating the synthesis of TGF-β1 in depressed patients (Sutcigil et al, 2007).…”

A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease

“…TGF-β1 is a neurotrophic factor whose deficit exerts a key role in AD. A selective impairment of TGF-β1 pathway is present in early AD, both in the AD brain (121,122) and in AD animal models (71,123,124). This deficit seems to critically contribute to neuroinflammation in AD brain.…”

“…Aβ, amyloid beta; Aβ 1−42 , 42-amino acid-long amyloid beta peptide; BDNF, brain-derived neurotrophic factor; IL-1β, interleukin-1 beta; MMP-9, metalloprotease-9; NGF, nerve growth factor; mNGF, mature nerve growth factor; proNGF, precursor of the nerve growth factor; RNS, reactive nitrogen species; ROS, reactive oxygen species; TGF-β, transforming growth factor-beta; TNF-α, tumor necrosis factor-alpha. produce and release proinflammatory cytokines (14,68) and also by interfering with the synthesis of anti-inflammatory cytokines, for instance the transforming growth factor-beta 1 (TGF-β1) ( Figure 2) (69)(70)(71). This early proinflammatory process is characterized by neuronal and microglia-derived cytokines and chemokines as well as by mobilization of microglia toward Aβ-burdened neurons (Figure 2) (19,72).…”