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/metabolismoRESUMO
Type 2 diabetes (T2D) is an important risk factor to suffer dementia, including Alzheimer's disease (AD), and some neuropathological features observed in dementia could be mediated by T2D metabolic alterations. Since brain atrophy and impaired neurogenesis have been observed both T2D and AD we analyzed central nervous system (CNS) morphological alterations in the db/db mice (leptin receptor KO mice), as a model of long-term insulin resistance and T2D, and in C57Bl6 mice fed with high fat diet (HFD), as a model of diet induced insulin resistance and prediabetes. Db/db mice showed an age-dependent cortical and hippocampal atrophy, whereas in HFD mice cortex and hippocampus were preserved. We also detected increased neurogenesis and cell proliferation rates in young db/db mice when compared with control littermates. Our study shows that metabolic parameters serve as predictors of both atrophy and altered proliferation and neurogenesis in the CNS. Moreover in the cortex, atrophy, cell proliferation and neurogenesis were significantly correlated. Our data suggest that T2D may underline some of the pathological features observed in the dementia process. They also support that blood glucose control in elderly patients could help to slow down dementia evolution and maybe, improve its prognosis.
