Altered Insulin Signaling in Alzheimer’s Disease Brain – Special Emphasis on PI3K-Akt Pathway
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. Insuli...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-06-01
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| Series: | Frontiers in Neuroscience |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fnins.2019.00629/full |
| _version_ | 1819102146898952192 |
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| author | Sami Gabbouj Simo Ryhänen Mikael Marttinen Rebekka Wittrahm Mari Takalo Susanna Kemppainen Henna Martiskainen Heikki Tanila Annakaisa Haapasalo Mikko Hiltunen Teemu Natunen |
| author_facet | Sami Gabbouj Simo Ryhänen Mikael Marttinen Rebekka Wittrahm Mari Takalo Susanna Kemppainen Henna Martiskainen Heikki Tanila Annakaisa Haapasalo Mikko Hiltunen Teemu Natunen |
| author_sort | Sami Gabbouj |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T01:29:56Z |
| format | Article |
| id | doaj.art-15215aa0ee3d4acfb1f0bd56cde7b958 |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-12-22T01:29:56Z |
| publishDate | 2019-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj.art-15215aa0ee3d4acfb1f0bd56cde7b9582022-12-21T18:43:30ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2019-06-011310.3389/fnins.2019.00629456800Altered Insulin Signaling in Alzheimer’s Disease Brain – Special Emphasis on PI3K-Akt PathwaySami Gabbouj0Simo Ryhänen1Mikael Marttinen2Rebekka Wittrahm3Mari Takalo4Susanna Kemppainen5Henna Martiskainen6Heikki Tanila7Annakaisa Haapasalo8Mikko Hiltunen9Teemu Natunen10Institute of Biomedicine, University of Eastern Finland, Kuopio, FinlandInstitute of Biomedicine, University of Eastern Finland, Kuopio, FinlandInstitute of Biomedicine, University of Eastern Finland, Kuopio, FinlandInstitute of Biomedicine, University of Eastern Finland, Kuopio, FinlandInstitute of Biomedicine, University of Eastern Finland, Kuopio, FinlandInstitute of Biomedicine, University of Eastern Finland, Kuopio, FinlandInstitute of Biomedicine, University of Eastern Finland, Kuopio, FinlandA.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, FinlandA.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, FinlandInstitute of Biomedicine, University of Eastern Finland, Kuopio, FinlandInstitute of Biomedicine, University of Eastern Finland, Kuopio, FinlandAlzheimer’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.https://www.frontiersin.org/article/10.3389/fnins.2019.00629/fullAlzheimer’s diseasetype 2 diabetesinsulinphosphatidylinositol-45-bisphosphate 3-kinase (PI3K)Akt (Protein kinase B |
| spellingShingle | Sami Gabbouj Simo Ryhänen Mikael Marttinen Rebekka Wittrahm Mari Takalo Susanna Kemppainen Henna Martiskainen Heikki Tanila Annakaisa Haapasalo Mikko Hiltunen Teemu Natunen Altered Insulin Signaling in Alzheimer’s Disease Brain – Special Emphasis on PI3K-Akt Pathway Frontiers in Neuroscience Alzheimer’s disease type 2 diabetes insulin phosphatidylinositol-4 5-bisphosphate 3-kinase (PI3K) Akt (Protein kinase B |
| title | Altered Insulin Signaling in Alzheimer’s Disease Brain – Special Emphasis on PI3K-Akt Pathway |
| title_full | Altered Insulin Signaling in Alzheimer’s Disease Brain – Special Emphasis on PI3K-Akt Pathway |
| title_fullStr | Altered Insulin Signaling in Alzheimer’s Disease Brain – Special Emphasis on PI3K-Akt Pathway |
| title_full_unstemmed | Altered Insulin Signaling in Alzheimer’s Disease Brain – Special Emphasis on PI3K-Akt Pathway |
| title_short | Altered Insulin Signaling in Alzheimer’s Disease Brain – Special Emphasis on PI3K-Akt Pathway |
| title_sort | altered insulin signaling in alzheimer s disease brain special emphasis on pi3k akt pathway |
| topic | Alzheimer’s disease type 2 diabetes insulin phosphatidylinositol-4 5-bisphosphate 3-kinase (PI3K) Akt (Protein kinase B |
| url | https://www.frontiersin.org/article/10.3389/fnins.2019.00629/full |
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