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Psychoneuroendocrinology ; 48: 123-35, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24998414

RESUMO

Age remains the main risk factor for developing Alzheimer's disease (AD) although certain metabolic alterations, including prediabetes and hyperinsulinemia, also increase this risk. We present a mouse model of AD (APPswe/PS1dE9 mouse) with severe hyperinsulinemia induced by long-term high fat diet (HFD) treatment. After 23 weeks on HFD learning and memory processes were compromised. We observed a significant increase in tau hyperphosphorylation and Aß pathology, including Aß levels and amyloid burden. Microglia activation was also significantly increased in HFD-treated mice, both in close proximity to and far from senile plaques. Insulin degrading enzyme and neprilysin levels were not affected, suggesting that Aß degradation pathways were preserved, whereas we detected an increase in spontaneous cortical bleeding that could underlay an impairment of Aß interstitial fluid drainage, contributing to the increase in Aß deposition in APP/PS1-HFD mice. Altogether our data suggest that early hyperinsulinemia is enough to exacerbate AD pathology observed in APP/PS1 mice, and supports the role of insulin-resistance therapies to stop or delay central complications associated.


Assuntos
Doença de Alzheimer/complicações , Precursor de Proteína beta-Amiloide/genética , Angiopatias Diabéticas/etiologia , Estado Pré-Diabético/complicações , Estado Pré-Diabético/fisiopatologia , Presenilina-1/genética , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/fisiopatologia , Dieta Hiperlipídica , Modelos Animais de Doenças , Progressão da Doença , Hiperinsulinismo/etiologia , Hiperinsulinismo/metabolismo , Resistência à Insulina , Aprendizagem em Labirinto , Memória , Camundongos , Camundongos Transgênicos , Estado Pré-Diabético/metabolismo , Proteínas tau/metabolismo
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