Dataset Information

Icariin Attenuates Amyloid-? (A?)-Induced Neuronal Insulin Resistance Through PTEN Downregulation.

ABSTRACT: Neuronal insulin resistance is implicated in neurodegenerative diseases. Icariin has been reported to improve insulin resistance in skeletal muscle cells and to restore impaired hypothalamic insulin signaling in the rats with chronic unpredictable mild stress. In addition, icariin can exert the neuroprotective effects in the mouse models of neurodegenerative diseases. However, the molecular mechanisms by which icariin affects neuronal insulin resistance are poorly understood. In the present study, amyloid-? (A?) was used to induce insulin resistance in human neuroblastoma SK-N-MC cells. Insulin sensitivity was evaluated by measuring insulin-stimulated Akt T308 phosphorylation and glucose uptake. We found that the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) mediated A?-induced insulin resistance. Icariin treatment markedly reduced A?-enhanced PTEN protein levels, leading to an improvement in A?-induced insulin resistance. Accordingly, PTEN overexpression obviously abolished the protective effects of icariin on A?-induced insulin resistance. Furthermore, icariin activated proteasome activity. The proteasome inhibitor MG132 attenuated the effects of icariin on PTEN protein levels. Taken together, these results suggest that icariin protects SK-N-MC cells against A?-induced insulin resistance by activating the proteasome-dependent degradation of PTEN. These findings provide an experimental background for the identification of novel molecular targets of icariin, which may help in the development of alternative therapeutic approaches for neurodegenerative diseases.

SUBMITTER: Zou X

PROVIDER: S-EPMC7296100 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Icariin Attenuates Amyloid-β (Aβ)-Induced Neuronal Insulin Resistance Through PTEN Downregulation.

Zou Xiaomei X Feng Xiyao X Fu Yalin Y Zheng Yuyang Y Ma Mingke M Wang Changhua C Zhang Yemin Y

Frontiers in pharmacology 20200609

Neuronal insulin resistance is implicated in neurodegenerative diseases. Icariin has been reported to improve insulin resistance in skeletal muscle cells and to restore impaired hypothalamic insulin signaling in the rats with chronic unpredictable mild stress. In addition, icariin can exert the neuroprotective effects in the mouse models of neurodegenerative diseases. However, the molecular mechanisms by which icariin affects neuronal insulin resistance are poorly understood. In the present stud ...[more]

PMID: 32581820

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Project description:BackgroundThe deposition of the amyloid β-peptide (Aβ) in the brain is one of the hallmarks of Alzheimer's disease (AD). It is not yet clear whether Aβ always leads to similar changes or whether it induces different features of neurodegeneration in relation to its intra- and/or extracellular localization or to its intracellular trafficking routes. To address this question, we have analyzed two transgenic mouse models: APP48 and APP23 mice. The APP48 mouse expresses Aβ1-42 with a signal sequence in neurons. These animals produce intracellular Aβ independent of amyloid precursor protein (APP) but do not develop extracellular Aβ plaques. The APP23 mouse overexpresses human APP with the Swedish mutation (KM670/671NL) in neurons and produces APP-derived extracellular Aβ plaques and intracellular Aβ aggregates.ResultsTracing of commissural neurons in layer III of the frontocentral cortex with the DiI tracer revealed no morphological signs of dendritic degeneration in APP48 mice compared to littermate controls. In contrast, the dendritic tree of highly ramified commissural frontocentral neurons was altered in 15-month-old APP23 mice. The density of asymmetric synapses in the frontocentral cortex was reduced in 3- and 15-month-old APP23 but not in 3- and 18-month-old APP48 mice. Frontocentral neurons of 18-month-old APP48 mice showed an increased proportion of altered mitochondria in the soma compared to wild type and APP23 mice. Aβ was often seen in the membrane of neuronal mitochondria in APP48 mice at the ultrastructural level.ConclusionsThese results indicate that APP-independent intracellular Aβ accumulation in APP48 mice is not associated with dendritic and neuritic degeneration but with mitochondrial alterations whereas APP-derived extra- and intracellular Aβ pathology in APP23 mice is linked to dendrite degeneration and synapse loss independent of obvious mitochondrial alterations. Thus, Aβ aggregates in APP23 and APP48 mice induce neurodegeneration presumably by different mechanisms and APP-related production of Aβ may, thereby, play a role for the degeneration of neurites and synapses.

Dataset Information

Icariin Attenuates Amyloid-? (A?)-Induced Neuronal Insulin Resistance Through PTEN Downregulation.

Publications

Icariin Attenuates Amyloid-β (Aβ)-Induced Neuronal Insulin Resistance Through PTEN Downregulation.

Similar Datasets

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