Neuron and neuroblast numbers and cytogenesis in the dentate gyrus of aged APPswe/PS1dE9 transgenic mice: Effect of long-term treatment with paroxetine

Olesen, Louise Ørum; Sivasaravanaparan, Mithula; Severino, Maurizio; Babcock, Alicia; Bouzinova, Elena V.; West, Mark J.; Wiborg, Ove; Finsen, Bente

doi:10.1016/j.nbd.2017.04.021

Cited by 15 publications

(17 citation statements)

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“…We observed no changes in the levels of Aβ40 or Aβ42 in the hippocampus of escitalopram-treated compared with vehicle-treated mice. Our observations differ from recent clinical and in vivo studies in which researchers have reported Aβ-reducing effects of chronic and acute antidepressant treatment [ 24 , 25 , 32 , 33 , 40 ], although others have also been unable to detect such Aβ-reducing effects [ 38 , 41 ]. Human subjects with a history of antidepressant drug treatment showed reduced cortical amyloid load compared with non-treated subjects, estimated by positron emission computed tomographic imaging using the amyloid-binding [ 11 C]-Pittsburgh compound B (PIB) radioligand [ 24 ].…”

Section: Discussioncontrasting

confidence: 99%

“…for 28 days has furthermore been shown to completely inhibit the growth of plaques without affecting their elimination [ 32 ]. Results at our own laboratory have suggested, however, that 9-month treatment with paroxetine (30 mg/kg/day being reduced to 10 mg/kg/day and ultimately 5 mg/kg/day) per os has no effect on plaque load in the neocortex of 18-month-old APP/PS1 mice [ 41 ], although a significant effect was observed in the hippocampus of the same mice [ 40 ]. Although these findings suggest that a high dosage of paroxetine may have an effect on plaque load at least in the hippocampus, they at the same time emphasise that paroxetine treatment by no means ameliorates plaque load when administered to aging mice in which the amyloid plaques are well-developed.…”

Section: Discussionmentioning

confidence: 99%

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Serotonin augmentation therapy by escitalopram has minimal effects on amyloid-β levels in early-stage Alzheimer’s-like disease in mice

et al. 2017

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BackgroundDysfunction of the serotonergic (5-HTergic) system has been implicated in the cognitive and behavioural symptoms of Alzheimer’s disease (AD). Accumulation of toxic amyloid-β (Aβ) species is a hallmark of AD and an instigator of pathology. Serotonin (5-HT) augmentation therapy by treatment with selective serotonin reuptake inhibitors (SSRIs) in patients with AD has had mixed success in improving cognitive function, whereas SSRI administration to mice with AD-like disease has been shown to reduce Aβ pathology. The objective of this study was to investigate whether an increase in extracellular levels of 5-HT induced by chronic SSRI treatment reduces Aβ pathology and whether 5-HTergic deafferentation of the cerebral cortex could worsen Aβ pathology in the APPswe/PS1ΔE9 (APP/PS1) mouse model of AD.MethodsWe administered a therapeutic dose of the SSRI escitalopram (5 mg/kg/day) in the drinking water of 3-month-old APP/PS1 mice to increase levels of 5-HT, and we performed intracerebroventricular injections of the neurotoxin 5,7-dihydroxytryptamine (DHT) to remove 5-HTergic afferents. We validated the effectiveness of these interventions by serotonin transporter autoradiography (neocortex 79.7 ± 7.6%) and by high-performance liquid chromatography for 5-HT (neocortex 64% reduction). After 6 months of escitalopram treatment or housing after DHT-induced lesion, we evaluated brain tissue by mesoscale multiplex analysis and sections by IHC analysis.ResultsAmyloid-β-containing plaques had formed in the neocortex and hippocampus of 9-month-old APP/PS1 mice after 6 months of escitalopram treatment and 5-HTergic deafferentation. Unexpectedly, levels of insoluble Aβ42 were unaffected in the neocortex and hippocampus after both types of interventions. Levels of insoluble Aβ40 increased in the neocortex of SSRI-treated mice compared with those treated with vehicle control, but they were unaffected in the hippocampus. 5-HTergic deafferentation was without effect on the levels of insoluble/soluble Aβ42 and Aβ40 in both the neocortex and hippocampus. However, levels of soluble amyloid precursor protein α were reduced in the neocortex after 5-HTergic deafferentation.ConclusionsBecause this study shows that modulation of the 5-HTergic system has either no effect or increases levels of insoluble/soluble Aβ42 and Aβ40 in the cerebral cortex of APP/PS1 mice, our observations do not support 5-HT augmentation therapy as a preventive strategy for reducing Aβ pathology.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-017-0298-y) contains supplementary material, which is available to authorized users.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Serotonin augmentation therapy by escitalopram has minimal effects on amyloid-β levels in early-stage Alzheimer’s-like disease in mice

et al. 2017

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“…IGF-1 has previously been shown to modulate hippocampal neurogenesis (Aberg et al, 2000, 2003; Anderson et al, 2002), and the cell type showing the most intense ISH signal for IGF-1 mRNA, across ages and genotypes, were the neuroblast-like cells in the sgz. With their characteristic distribution and morphology these cells resembled the doublecortin-expressing neuroblasts which we showed are reduced in 18-month-, but not 9- or 3-month-old male APP swe /PS1 ΔE9 Tg mice (Olesen et al, 2017). Enhancing microglial expression of IGF-1 in 9- to 10-month-old APP K95N , M591L /PS1 ΔE9 Tg mice by glatiramer acetate treatment was previously suggested as a mechanism to enhance neurogenesis and counteract learning deficits (Butovsky et al, 2006).…”

Section: Discussionmentioning

confidence: 59%

“…The APP swe /PS1 ΔE9 Tg mouse, which develops Aβ plaques in the hippocampus from 3 months of age (Hamilton and Holscher, 2012), has been reported to have more pronounced loss of sgz cell proliferation with age than age-matched wild-type (WT) mice by some groups (Demars et al, 2010; Valero et al, 2011; Hamilton and Holscher, 2012). Results by us showed a reduced number of neuroblasts in the sgz of male 18-month-old APP swe /PS1 ΔE9 Tg mice, while sgz cell proliferation was unaffected by genotype (Olesen et al, 2017).…”

Section: Introductionmentioning

confidence: 87%

Microglia Express Insulin-Like Growth Factor-1 in the Hippocampus of Aged APPswe/PS1ΔE9 Transgenic Mice

Myhre

Thygesen

Villadsen

et al. 2019

Front. Cell. Neurosci.

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Insulin-like growth factor-1 (IGF-1) is a pleiotropic molecule with neurotrophic and immunomodulatory functions. Knowing the capacity of chronically activated microglia to produce IGF-1 may therefore show essential to promote beneficial microglial functions in Alzheimer’s disease (AD). Here, we investigated the expression of IGF-1 mRNA and IGF-1 along with the expression of tumor necrosis factor (TNF) mRNA, and the amyloid-β (Aβ) plaque load in the hippocampus of 3- to 24-month-old APP swe /PS1 ΔE9 transgenic (Tg) and wild-type (WT) mice. As IGF-1, in particular, is implicated in neurogenesis we also monitored the proliferation of cells in the subgranular zone (sgz) of the dentate gyrus. We found that the Aβ plaque load reached its maximum in aged 21- and 24-month-old APP swe /PS1 ΔE9 Tg mice, and that microglial reactivity and hippocampal IGF-1 and TNF mRNA levels were significantly elevated in aged APP swe /PS1 ΔE9 Tg mice. The sgz cell proliferation decreased with age, regardless of genotype and increased IGF-1/TNF mRNA levels. Interestingly, IGF-1 mRNA was expressed in subsets of sgz cells, likely neuroblasts, and neurons in both genotypes, regardless of age, as well as in glial-like cells. By double in situ hybridization these were shown to be IGF1 mRNA + CD11b mRNA + cells, i.e., IGF-1 mRNA-expressing microglia. Quantification showed a 2-fold increase in the number of microglia and IGF-1 mRNA-expressing microglia in the molecular layer of the dentate gyrus in aged APP swe /PS1 ΔE9 Tg mice. Double-immunofluorescence showed that IGF-1 was expressed in a subset of Aβ plaque-associated CD11b + microglia and in several subsets of neurons. Exposure of primary murine microglia and BV2 cells to Aβ 42 did not affect IGF-1 mRNA expression. IGF-1 mRNA levels remained constant in WT mice with aging, unlike TNF mRNA levels which increased with aging. In conclusion, our results suggest that the increased IGF-1 mRNA levels can be ascribed to a larger number of IGF-1 mRNA-expressing microglia in the aged APP swe /PS1 ΔE9 Tg mice. The finding that subsets of microglia retain the capacity to express IGF-1 mRNA and IGF-1 in the aged APP swe /PS1 ΔE9 Tg mice is encouraging, considering the beneficial therapeutic potential of modulating microglial production of IGF-1 in AD.

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“…Previous studies have found the effects of SSIRs on synaptic plasticity which was impaired in AD model [5], for example, fluoxetine has been found to facilitate LTP in the cerebral cortex, hippocampus and basolateral amygdala [23,46]. Previous report has also examined the effect of long-term treatment with paroxetine on the neurogenic process in hippocampus, while no difference was observed in DCX + (doublecortin) neuroblast number between WT and AD mice from postnatal 3 to 9 months, suggesting that the beneficial effects of Paroxetine may not due to neurogenesis [47].…”

Section: Discussionmentioning

confidence: 99%

Paroxetine ameliorates prodromal emotional dysfunction and late-onset memory deficit in Alzheimer’s disease mice

Chen

Liu

et al. 2020

Transl Neurodegener

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Background: Neuropsychiatric symptoms (NPS) such as depression, anxiety, apathy, and irritability occur in prodromal phases of clinical Alzheimer's disease (AD), which might be an increased risk for later developing AD. Here we treated young APP/PS1 AD model mice prophylactically with serotonin-selective re-uptake inhibitor (SSRI) paroxetine and investigated the protective role of anti-depressant agent in emotional abnormalities and cognitive defects during disease progress. Methods: To investigate the protective role of paroxetine in emotional abnormalities and cognitive defects during disease progress, we performed emotional behaviors of 3 months old APP/PS1 mouse following oral administration of paroxetine prophylactically starting at 1 month of age. Next, we tested the cognitive, biochemical and pathological, effects of long term administration of paroxetine at 6 months old. Results: Our results showed that AD mice displayed emotional dysfunction in the early stage. Prophylactic administration of paroxetine ameliorated the initial emotional abnormalities and preserved the eventual memory function in AD mice. Conclusion: Our data indicate that prophylactic administration of paroxetine ameliorates the emotional dysfunction and memory deficit in AD mice. These neuroprotective effects are attributable to functional restoration of glutamate receptor (GluN2A) in AD mice.

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Neuron and neuroblast numbers and cytogenesis in the dentate gyrus of aged APPswe/PS1dE9 transgenic mice: Effect of long-term treatment with paroxetine

Cited by 15 publications

References 73 publications

Serotonin augmentation therapy by escitalopram has minimal effects on amyloid-β levels in early-stage Alzheimer’s-like disease in mice

Serotonin augmentation therapy by escitalopram has minimal effects on amyloid-β levels in early-stage Alzheimer’s-like disease in mice

Microglia Express Insulin-Like Growth Factor-1 in the Hippocampus of Aged APPswe/PS1ΔE9 Transgenic Mice

Paroxetine ameliorates prodromal emotional dysfunction and late-onset memory deficit in Alzheimer’s disease mice

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