Can Animal Models Inform on the Relationship between Depression and Alzheimer Disease?

Nyarko, Jennifer N.K.; Quartey, Maa O.; Baker, Glen B.; Mousseau, Darrell D.

doi:10.1177/0706743718772514

Cited by 8 publications

(8 citation statements)

References 177 publications

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“…We used this non-Tg model of AD to study the neurobiological links between depression and AD and the role of Aβ oligomers in the pathophysiology of amyloid-related depression, a recently identified clinical phenotype characterized by a low response to “monoaminergic antidepressants in depressed patients with an high risk to develop AD” (Li et al, 2017). Mimicking this clinical phenotype in rodents is a difficult challenge (Nyarko et al, 2019) but also an essential step to improve drug discovery processes in AD and explore the disease-modifying potential of antidepressant drugs in AD (Caraci et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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“…The tail suspension test was used as a measure of learned helplessness and depression-like behavior, which is seen in both humans with AD (Chi et al, 2014) and mouse models (Nyarko et al, 2019), including the 3xTg-AD mice, and have been linked to impaired monoamine transmission (Romano et al, 2014). In this study, 3xTg-AD mice treated with DWG-1036 froze less frequently than the 3xTg-AD mice that received the vehicle, whereas there were no differences between the treatment groups in WT mice.…”

Section: Discussionmentioning

confidence: 99%

Effects of the Novel IDO Inhibitor DWG-1036 on the Behavior of Male and Female 3xTg-AD Mice

et al. 2019

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The kynurenine pathway metabolizes tryptophan into nicotinamide adenine dinucleotide, producing a number of intermediary metabolites, including 3-hydroxy kynurenine and quinolinic acid, which are involved in the neurodegenerative mechanisms that underlie Alzheimer’s disease (AD). Indolamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme of this pathway, is increased in AD, and it has been hypothesized that blocking this enzyme may slow the progression of AD. In this study, we treated male and female 3xTg-AD and wild-type mice with the novel IDO inhibitor DWG-1036 (80 mg/kg) or vehicle (distilled water) from 2 to 6 months of age and then tested them in a battery of behavioral tests that measured spatial learning and memory (Barnes maze), working memory (trace fear conditioning), motor coordination and learning (rotarod), anxiety (elevated plus maze), and depression (tail suspension test). The 3xTg-AD mice treated with DWG-1036 showed better memory in the trace fear conditioning task and significant improvements in learning but poorer spatial memory in the Barnes maze. DWG-1036 treatment also ameliorated the behaviors associated with increased anxiety in the elevated plus maze and depression-like behaviors in the tail suspension test in 3xTg-AD mice. However, the effects of DWG-1036 treatment on the behavioral tasks were variable, and sex differences were apparent. In addition, high doses of DWG-1036 resulted in reduced body weight, particularly in females. Taken together, our results suggest that the kynurenine pathway is a promising target for treating AD, but more work is needed to determine the effective compounds, examine sex differences, and understand the side effects of the compounds.

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“…Preclinical and clinical studies have indicated that depression is a risk factor for cognitive decline and AD, while depressive symptoms manifest in 30% of patients diagnosed with AD. , Because of the association between elevated tau burden and depression, we sought to determine whether pathological tau in 5-HT neurons results in depression-like symptoms, including behavioral despair or anhedonia. 5 to 6 weeks after surgery, ePet1 hTauP301L mice and controls were subjected to tail suspension and forced swim tests.…”

Section: Resultsmentioning

confidence: 99%

Behavioral and Neurophysiological Implications of Pathological Human Tau Expression in Serotonin Neurons

Khan,

Uribe Isaza,

Rouhi

et al. 2024

ACS Chem. Neurosci.

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Alzheimer's disease (AD) is a progressive degenerative disorder that results in a severe loss of brain cells and irreversible cognitive decline. Memory problems are the most recognized symptoms of AD. However, approximately 90% of patients diagnosed with AD suffer from behavioral symptoms, including mood changes and social impairment years before cognitive dysfunction. Recent evidence indicates that the dorsal raphe nucleus (DRN) is among the initial regions that show tau pathology, which is a hallmark feature of AD. The DRN harbors serotonin (5-HT) neurons, which are critically involved in mood, social, and cognitive regulation. Serotonergic impairment early in the disease process may contribute to behavioral symptoms in AD. However, the mechanisms underlying vulnerability and contribution of the 5-HT system to AD progression remain unknown. Here, we performed behavioral and electrophysiological characterizations in mice expressing a phosphorylation-prone form of human tau (hTauP301L) in 5-HT neurons. We found that pathological tau expression in 5-HT neurons induces anxiety-like behavior and alterations in stress-coping strategies in female and male mice. Female mice also exhibited social disinhibition and mild cognitive impairment in response to 5-HT neuron-specific hTauP301L expression. Behavioral alterations were accompanied by disrupted 5-HT neuron physiology in female and male hTauP301L expressing mice with exacerbated excitability disruption in females only. These data provide mechanistic insights into the brain systems and symptoms impaired early in AD progression, which is critical for disease intervention.

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Can Animal Models Inform on the Relationship between Depression and Alzheimer Disease?

Cited by 8 publications

References 177 publications

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

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

Effects of the Novel IDO Inhibitor DWG-1036 on the Behavior of Male and Female 3xTg-AD Mice

Behavioral and Neurophysiological Implications of Pathological Human Tau Expression in Serotonin Neurons

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