PTEN levels in Alzheimer's disease medial temporal cortex

Rickle, Annika; Bogdanović, Nenad; Volkmann, Inga; Zhou, Xin‐Wen; Pei, Jin-Jing; Winblad, Bengt; Cowburn, Richard F.

doi:10.1016/j.neuint.2005.08.014

Cited by 36 publications

(25 citation statements)

References 38 publications

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“…However, another study showed that acute exposure of primary mouse neurons to Aβ42 up-regulated Akt phosphorylation (27). More importantly, an increase in Akt activity was found in the temporal cortex of the postmortem AD brain, suggesting an upregulated PI3K/Akt pathway in patients (28)(29)(30). Consistent with the postmortem study, our in vivo analysis revealed that accumulation of Aβ42 seemed to increase PI3K activity at the larval NMJ, larval ganglion neurons, and the adult brain.…”

Section: Discussionsupporting

confidence: 86%

PI3 kinase signaling is involved in Aβ-induced memory loss in Drosophila

Chiang

Wang

Xie³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

112

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Multiple intracellular signals are altered in Alzheimer's disease brain tissues, including the PI3K/Akt pathway. However, the pathological relevance of such alterations is poorly understood. In vitro studies yield results that seem to be consistent with the conventional perception in which an up-regulation of the cell survival pathway, PI3K pathway, is protective in Alzheimer's disease pathogenesis. The current in vivo genetic approach, however, reveals that inhibition of the PI3K pathway leads to rescuing of the β-amyloid peptide (Aβ)-induced memory loss in the Drosophila brain. We began our inquiry into the molecular basis of this memory loss by studying Aβ42-induced enhancement of long-term depression. We found that long-term depression is restored to a normal level through inhibition of PI3K activity. Aβ42-induced PI3K hyperactivity is directly confirmed by immunostaining of the PI3K phosphorylation targets, phospholipids. Such observations lead to the following demonstration that Aβ42-induced memory loss can be rescued through genetic silencing or pharmacological inhibition of PI3K functions. Our data suggest that Aβ42 stimulates PI3K, which in turn causes memory loss in association with an increase in accumulation of Aβ42 aggregates.

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Section: Discussionsupporting

confidence: 86%

PI3 kinase signaling is involved in Aβ-induced memory loss in Drosophila

Chiang

Wang

Xie³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

112

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“…Cdc25A and Cdc25B are activated in the degenerating postmitotic neurons of AD patients (65,66). PTEN, a major negative regulator of the PI3k/Akt pathway, was found to be significantly less expressed in AD neurons, as well as being altered in distribution (49,67). However the underlying mechanism governing altered phosphatase activity remains to be investigated.…”

Section: +mentioning

confidence: 99%

Aberrant phosphorylation in the pathogenesis of Alzheimer's disease

Chung

2009

BMB Reports

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“…Clinical manifestations of inherited PTEN mutation occur with highly variable penetrance and also include benign hamartomas in multiple tissues, macrocephaly, seizures, ataxia, mental retardation and autism in addition to cancer predisposition (Ali et al, 1999, Goffin et al, 2001, Eng, 2003, Butler et al, 2005. Changes in PTEN levels have recently been linked to Alzheimer's disease (Zori et al, 1998, Goffin et al, 2001, Butler et al, 2005, Griffin et al, 2005, Rickle et al, 2006. While the tumor suppressor activity of Pten has been extensively studied in multiple tissue types, work relating Pten loss of function to neuronal dysfunction has only recently been studied.…”

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confidence: 99%

Phosphatase and tensin homolog, deleted on chromosome 10 deficiency in brain causes defects in synaptic structure, transmission and plasticity, and myelination abnormalities

et al. 2008

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The phosphatidylinositol 3-kinase (PI3K) signaling pathway modulates growth, proliferation and cell survival in diverse tissue types and plays specialized roles in the nervous system including influences on neuronal polarity, dendritic branching and synaptic plasticity. The tumor-suppressor phosphatase with tensin homology (PTEN) is the central negative regulator of the PI3K pathway. Germline PTEN mutations result in cancer predisposition, macrocephaly and benign hamartomas in many tissues, including Lhermitte-Duclos disease, a cerebellar growth disorder. Neurological abnormalities including autism, seizures and ataxia have been observed in association with inherited PTEN mutation with variable penetrance. It remains unclear how loss of PTEN activity contributes to neurological dysfunction. To explore the effects of Pten deficiency on neuronal structure and function, we analyzed several ultra-structural features of Pten-deficient neurons in Pten conditional knockout mice. Using Golgi stain to visualize full neuronal morphology, we observed that increased size of nuclei and somata in Pten-deficient neurons was accompanied by enlarged caliber of neuronal projections and increased dendritic spine density. Electron microscopic evaluation revealed enlarged abnormal synaptic structures in the cerebral cortex and cerebellum. Severe myelination defects included thickening and unraveling of the myelin sheath surrounding hypertrophic axons in the corpus callosum. Defects in myelination of axons of normal caliber were observed in the cerebellum, suggesting intrinsic abnormalities in Pten-deficient oligodendrocytes. We did not observe these abnormalities in wild-type or conditional Pten heterozygous mice. Moreover, conditional deletion of Pten drastically weakened synaptic transmission and synaptic plasticity at excitatory synapses between CA3 and CA1 pyramidal neurons in the hippocampus. These data suggest that Pten is involved in mechanisms that control development of neuronal and synaptic structures and subsequently synaptic function. KeywordsPTEN; PI3K; brain; neurons; myelin; hypertrophy; synaptic plasticityThe tumor suppressor PTEN (phosphatase and tensin homolog, deleted on chromosome 10) is important in the modulation of cell growth, proliferation and survival. Inactivating mutations in both alleles of PTEN occur in diverse tumor types including glioblastoma multiforme (Chow and Baker, 2006). Consistent with the two-hit hypothesis of tumor suppression, inherited mutations in PTEN are associated with cancer predisposition, and the second allele of PTEN *To whom correspondence should be addressed: Suzanne.Baker@stjude.org; Phone: (901) 495-2254; FAX: (901) 495-2270. Section Editor: John L.R. Rubenstein, Developmental Neuroscience Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof bef...

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PTEN levels in Alzheimer's disease medial temporal cortex

Cited by 36 publications

References 38 publications

PI3 kinase signaling is involved in Aβ-induced memory loss in Drosophila

PI3 kinase signaling is involved in Aβ-induced memory loss in Drosophila

Aberrant phosphorylation in the pathogenesis of Alzheimer's disease

Phosphatase and tensin homolog, deleted on chromosome 10 deficiency in brain causes defects in synaptic structure, transmission and plasticity, and myelination abnormalities

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