Intranasal insulin activates Akt2 signaling pathway in the hippocampus of wild-type but not in APP/PS1 Alzheimer model mice

Gabbouj, Sami; Natunen, Teemu; Koivisto, Hennariikka; Jokivarsi, Kimmo; Takalo, Mari; Marttinen, Mikael; Wittrahm, Rebekka; Kemppainen, Susanna; Naderi, Reyhaneh; Posado-Fernández, Adrián; Ryhänen, Simo; Mäkinen, Petra; Paldanius, Kaisa M. A.; Dória, Gonçalo; Poutiainen, Pekka; Flores, Orfeu; Haapasalo, Annakaisa; Tanila, Heikki; Hiltunen, Mikko

doi:10.1016/j.neurobiolaging.2018.11.008

Cited by 27 publications

(11 citation statements)

References 53 publications

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“…Neurotoxic neuronal-microglial interactions have been implicated in the development of ad (32). The production of inflammatory cytokines secreted by activated microglia led to neuron apoptosis (33). in the present study, Ta decreasedcaspase-3 activity and dna fragmentation levels in the PFc and HC of AD mice.…”

Section: Discussionsupporting

confidence: 53%

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Neuroprotective effect of tormentic acid against memory impairment and neuro‑inflammation in an Alzheimer's disease mouse model

Cui

Sun

et al. 2020

Mol Med Rep

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cognitive impairment and neuro-inflammatory responses are the distinctive characteristics of alzheimer's disease (ad). Tormentic acid (Ta) is one of the major active components of Potentilla chinensis and has been demonstrated to have anti-inflammatory properties. However, the potential effects of Ta on neuro-inflammatory responses and memory impairment in AD remain unknown. The present study investigated the therapeutic effect of Ta on neuro-inflammation, as well as learning and memory impairment in ad mice. in addition, the effects of Ta treatment were also examined in a co-culture system of microglia and primary neurons. intraperitoneal administration of Ta attenuated memory deficits in amyloid β precursor protein/presenilin 1 transgenic mice, with a marked decrease in amyloid plaque deposition. Ta also reduced microglial activation and decreased the secretion of pro-inflammatory factors in AD mice. Furthermore, pre-treatment with TA suppressed the production of pro-inflammatory markers, as well as the nuclear translocation of nuclear factor-κB (nF-κB) p65 induced by aβ exposure in BV2 cells. TA also reduced inhibited neurotoxicity and improved neuron survival in a neuron-microglia co-culture system. Taken together, these findings suggested that Ta could attenuate neuro-inflammation and memory impairment, which may be closely associated with regulation of the nF-κB pathway.

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Section: Discussionsupporting

confidence: 53%

“…10A and B). However, these effects were attenuated by pre-treatment with 10 nM TA before exposure to aβ [25][26][27][28][29][30][31][32][33][34][35] . Together, these results indicated that Ta suppression of il-1β and TnFα expression is most likely associated with inhibition of nF-κB activation.…”

Section: Resultsmentioning

confidence: 93%

Neuroprotective effect of tormentic acid against memory impairment and neuro‑inflammation in an Alzheimer's disease mouse model

Cui

Sun

et al. 2020

Mol Med Rep

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“…IN has been shown to activate PI3K-Akt signaling in the brain and to have beneficial effects in individuals with cognitive impairment (Mao et al, 2016; Chapman et al, 2017). IN was also shown to differentially alter the expression of homeostatic microglia markers in AD mice as compared to wild-type mice, suggesting that IN affects the function and activity of microglia depending on the disease status (Gabbouj et al, 2019). Collectively, these genetic and functional findings reinforce the idea that PI3K-Akt signaling cascade in glial cells encompasses a central role in different cellular processes affecting AD pathogenesis beyond its conventional functions in glucose uptake and metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…However, the effects appear to depend on the dose and the dose regime (acute vs. repeated), cognitive test used, and the APOE genotype. Interestingly, in a preclinical APP/PS1 AD mouse model, IN treatment led to the specific activation of the Akt2 isoform (Gabbouj et al, 2019). This suggests that Akt kinases may have isoform-specific roles in insulin signaling in the brain.…”

Section: Introductionmentioning

confidence: 99%

Altered Insulin Signaling in Alzheimer’s Disease Brain – Special Emphasis on PI3K-Akt Pathway

et al. 2019

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Alzheimer’s disease (AD) and type 2 diabetes (T2D) are both diseases with increasing prevalence in aging populations. T2D, characterized by insulin resistance and defective insulin signaling, is a common co-morbidity and a risk factor for AD, increasing the risk approximately two to fourfold. Insulin exerts a wide variety of effects as a growth factor as well as by regulating glucose, fatty acid, and protein metabolism. Certain lifestyle factors, physical inactivity and typical Western diet (TWD) containing high fat and high sugar are strongly associated with insulin resistance and T2D. The PI3K-Akt signaling pathway is a major mediator of effects of insulin and plays a crucial role in T2D pathogenesis. Decreased levels of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) subunits as well as blunted Akt kinase phosphorylation have been observed in the AD brain, characterized by amyloid-β and tau pathologies. Furthermore, AD mouse models fed with TWD have shown to display altered levels of PI3K subunits. How impaired insulin-PI3K-Akt signaling in peripheral tissues or in the central nervous system (CNS) affects the development or progression of AD is currently poorly understood. Interestingly, enhancement of PI3K-Akt signaling in the CNS by intranasal insulin (IN) treatment has been shown to improve memory in vivo in mice and in human trials. Insulin is known to augment neuronal growth and synapse formation through the PI3K-Akt signaling pathway. However, PI3K-Akt pathway mediates signaling related to different functions also in other cell types, like microglia and astrocytes. In this review, we will discuss the most prominent molecular mechanisms related to the PI3K-Akt pathway in AD and how T2D and altered insulin signaling may affect the pathogenesis of AD.

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“…Here, even in neonatal mice, treatment with intranasal insulin reduces anaesthesia-induced activation of neuronal apoptosis and a single dose of intranasal insulin can influence glucose metabolism by activating insulin signalling and decreasing autophagy in the hippocampus. 54,55 Furthermore, intranasal IGF-1 application also prevents neuronal death, in addition to decreasing neuroinflammation and oxidative stress, revealing the potent effect of insulin/IGF-1 signalling after intranasal application.…”

Section: The Interpl Ay Of In Sulin S Ig Nalling and Mitochondrial Fun C Ti On In The B R Ain Is Vital For Cell Me Tabolis M And Fun C Timentioning

confidence: 97%

Untangling the effect of insulin action on brain mitochondria and metabolism

Schell

Wardelmann

Kleinridders

2021

J Neuroendocrinology

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Intranasal insulin activates Akt2 signaling pathway in the hippocampus of wild-type but not in APP/PS1 Alzheimer model mice

Cited by 27 publications

References 53 publications

Neuroprotective effect of tormentic acid against memory impairment and neuro‑inflammation in an Alzheimer's disease mouse model

Neuroprotective effect of tormentic acid against memory impairment and neuro‑inflammation in an Alzheimer's disease mouse model

Altered Insulin Signaling in Alzheimer’s Disease Brain – Special Emphasis on PI3K-Akt Pathway

Untangling the effect of insulin action on brain mitochondria and metabolism

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