Direct pharmacological Akt activation rescues Alzheimer's disease like memory impairments and aberrant synaptic plasticity

Yi, Jee Hyun; Baek, Soo Ji; Heo, Sunghoo; Park, Hye Jin; Kwon, Huiyoung; Lee, Seungheon; Jung, Junhee; Park, Se Jin; Kim, Byung C.; Lee, Young Choon; Ryu, Jong Hoon; Kim, Dong Hyun

doi:10.1016/j.neuropharm.2017.10.028

Cited by 62 publications

(39 citation statements)

References 52 publications

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“…The activity of Akt/GSK3β and mitogen-activated protein kinases (MAPKs) were evaluated as the former is pivotal to cellular proliferation, growth, and survival in response to extracellular stimuli [52] and the latter playing a key part in regulating intracellular adaptions to various extracellular stimulation such as hyperosmosis, oxidative stress, and pro-inflammatory factors [52]. Aβ oligomer inhibits the PI3K/AKT pathway, and pharmacological activation of Akt activity reduces synaptic deficits and cognitive impairment in both 5XFAD and Aβ-induced AD mice [53]. Activities of GSK-3β, the downstream factor of Akt, is closely linked with tau hyperphosphorylation and memory dysfunction that triggered by soluble form of Amyloid-β [54].…”

Section: Discussionmentioning

confidence: 99%

Short-term resistance exercise inhibits neuroinflammation and attenuates neuropathological changes in 3xTg Alzheimer’s disease mice

Liu

Chu

Yan

et al. 2020

J Neuroinflammation

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Background: Both human and animal studies have shown beneficial effects of physical exercise on brain health but most tend to be based on aerobic rather than resistance type regimes. Resistance exercise has the advantage of improving both muscular and cardiovascular function, both of which can benefit the frail and the elderly. However, the neuroprotective effects of resistance training in cognitive impairment are not well characterized. Methods: We evaluated whether short-term resistant training could improve cognitive function and pathological changes in mice with pre-existing cognitive impairment. Nine-month-old 3xTg mouse underwent a resistance training protocol of climbing up a 1-m ladder with a progressively heavier weight loading. Results: Compared with sedentary counterparts, resistance training improved cognitive performance and reduced neuropathological and neuroinflammatory changes in the frontal cortex and hippocampus of mice. In line with these results, inhibition of pro-inflammatory intracellular pathways was also demonstrated. Conclusions: Short-term resistance training improved cognitive function in 3xTg mice, and conferred beneficial effects on neuroinflammation, amyloid and tau pathology, as well as synaptic plasticity. Resistance training may represent an alternative exercise strategy for delaying disease progression in Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

Short-term resistance exercise inhibits neuroinflammation and attenuates neuropathological changes in 3xTg Alzheimer’s disease mice

Liu

Chu

Yan

et al. 2020

J Neuroinflammation

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“…Previous studies have reported that Aβ peptide may decrease Akt phosphorylation, thus, inhibiting its activation (Hoppe et al, 2013a; Magrané et al, ). Furthermore, it was recently demonstrated that Akt could be a therapeutic target for memory impairment associated with AD, since the pharmacological activation of this protein was able to rescue memory impairment and aberrant synaptic plasticity in Aβ‐injected mice as well as in a transgenic AD mouse model (Yi et al, ). Reduced activation of Akt is known to decrease phosphorylation of GSK‐3β, which in turn induces Tau hyperphosphorylation, and eventually, cell death (Hemmings & Restuccia, ).…”

Section: Discussionmentioning

confidence: 99%

Genistein protects against amyloid‐beta‐induced toxicity in SH‐SY5Y cells by regulation of Akt and Tau phosphorylation

Petry

Coelho

Gaelzer

et al. 2019

Phytotherapy Research

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Alzheimer's disease is a neurodegenerative disorder characterized by extracellular deposition of amyloid‐β (Aβ) peptide and hyperphosphorylation of Tau protein, which ultimately leads to the formation of intracellular neurofibrillary tangles and cell death. Increasing evidence indicates that genistein, a soy isoflavone, has neuroprotective effects against Aβ‐induced toxicity. However, the molecular mechanisms involved in its neuroprotection are not well understood. In this study, we have established a neuronal damage model using retinoic‐acid differentiated SH‐SY5Y cells treated with different concentrations of Aβ25–35 to investigate the effect of genistein against Aβ‐induced cell death and the possible involvement of protein kinase B (PKB, also termed Akt), glycogen synthase kinase 3β (GSK‐3β), and Tau as an underlying mechanism to this neuroprotection. Differentiated SH‐SY5Y cells were pre‐treated for 24 hr with genistein (1 and 10 nM) and exposed to Aβ25–35 (25 μM), and we found that genistein partially inhibited Aβ induced cell death, primarily apoptosis. Furthermore, the protective effect of genistein was associated with the inhibition of Aβ‐induced Akt inactivation and Tau hyperphosphorylation. These findings reinforce the neuroprotective effects of genistein against Aβ toxicity and provide evidence that its mechanism may involve regulation of Akt and Tau proteins.

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“…Caspase-3 and GSK-3β inhibitors ameliorated memory impairments and synaptic deficits in Aβ-injected AD model mice. Recent evidence also found that pharmacological activation of Akt rescued memory impairments and aberrant synaptic plasticity in Aβ-injected mice AD [ 55 ]. However, our results suggest that resveratrol exerts effects similar to those of the Ang-II receptor antagonist losartan by attenuating Ang-II-induced tau pathologies, improving Akt activation, and attenuating down-regulation of the AT1R–Aβ–caspase 3–GSK-3β signalling pathway ( Figure 3 ).…”

Section: Discussionmentioning

confidence: 99%

Effect of Resveratrol on Reactive Oxygen Species-Induced Cognitive Impairment in Rats with Angiotensin II-Induced Early Alzheimer’s Disease †

Lin

Sun

et al. 2018

JCM

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Recent studies have indicated that several anti-hypertensive drugs may delay the development and progression of Alzheimer’s disease (AD). However, the relationships among AD, hypertension, and oxidative stress remain to be elucidated. Here, we aimed to determine whether reactive oxygen species (ROS) reduction by resveratrol in the brain leads to cognitive impairment reduction in rats with angiotensin II (Ang-II)-induced early AD. Male Wistar Kyoto (WKY) rats with Ang-II-induced AD were treated with losartan or resveratrol for two weeks. Our results show decreased blood pressure, increased hippocampal brain-derived neurotrophic factor (BDNF) level, and decreased nucleus tractus solitarius (NTS) ROS production in the Ang-II groups with losartan (10 mg/kg), or resveratrol (10 mg/kg/day) treatment. Furthermore, losartan inhibition of hippocampal TauT231 phosphorylation activated AktS473 phosphorylation, and significantly abolished Ang-II-induced Aβ precursors, active caspase 3, and glycogen synthase kinase 3β (GSK-3β)Y216 expressions. Consistently, resveratrol showed similar effects compared to losartan. Both losartan and resveratrol restored hippocampal-dependent contextual memory by NADPH oxidase 2 (NOX2) deletion and superoxide dismutase 2 (SOD2) elevation. Our results suggest that both losartan and resveratrol exert neuroprotective effects against memory impairment and hippocampal damage by oxidative stress reduction in early stage AD rat model. These novel findings indicate that resveratrol may represent a pharmacological option similar to losartan for patients with hypertension at risk of AD during old age.

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Direct pharmacological Akt activation rescues Alzheimer's disease like memory impairments and aberrant synaptic plasticity

Cited by 62 publications

References 52 publications

Short-term resistance exercise inhibits neuroinflammation and attenuates neuropathological changes in 3xTg Alzheimer’s disease mice

Short-term resistance exercise inhibits neuroinflammation and attenuates neuropathological changes in 3xTg Alzheimer’s disease mice

Genistein protects against amyloid‐beta‐induced toxicity in SH‐SY5Y cells by regulation of Akt and Tau phosphorylation

Effect of Resveratrol on Reactive Oxygen Species-Induced Cognitive Impairment in Rats with Angiotensin II-Induced Early Alzheimer’s Disease †

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