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Mechanisms Associated with Type 2 Diabetes as a Risk Factor for Alzheimer-Related Pathology

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Abstract

Current evidence suggests dementia and pathology in Alzheimer’s Disease (AD) are both dependent and independent of amyloid processing and can be induced by multiple ‘hits’ on vital neuronal functions. Type 2 diabetes (T2D) poses the most important risk factor for developing AD after ageing and dysfunctional IR/PI3K/Akt signalling is a major contributor in both diseases. We developed a model of T2D, coupling subdiabetogenic doses of streptozotocin (STZ) with a human junk food (HJF) diet to more closely mimic the human condition. Over 35 weeks, this induced classic signs of T2D (hyperglycemia and insulin dysfunction) and a modest, but stable deficit in spatial recognition memory, with very little long-term modification of proteins in or associated with IR/PI3K/Akt signalling in CA1 of the hippocampus. Intracerebroventricular infusion of soluble amyloid beta 42 (Aβ42) to mimic the early preclinical rise in Aβ alone induced a more severe, but short-lasting deficits in memory and deregulation of proteins. Infusion of Aβ on the T2D phenotype exacerbated and prolonged the memory deficits over approximately 4 months, and induced more severe aberrant regulation of proteins associated with autophagy, inflammation and glucose uptake from the periphery. A mild form of environmental enrichment transiently rescued memory deficits and could reverse the regulation of some, but not all protein changes. Together, these data identify mechanisms by which T2D could create a modest dysfunctional neuronal milieu via multiple and parallel inputs that permits the development of pathological events identified in AD and memory deficits when Aβ levels are transiently effective in the brain.

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Acknowledgements

This work was supported by the Centre National de la Recherche Scientifique (CNRS, France); LECMA Vaincre Alzheimer, France (12702) to SD; the Hungarian Brain Research Programme 2.0 (2017-1.2.1-NKP-2017-00002) and Economy Development and Innovation Operative Programme (GINOP 2.3.2_15_2016_00038) to LF and ZB. KN was supported by LECMA funding and MS by the China Scholarship Council.

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  1. Men Su

    Present address: Division of Episomal Persistent DNA in Cancer and Chronic disease, German Cancer Research Centre (DKFZ), 69120, Heidelberg, Germany

Authors and Affiliations

  1. Département Cognition & Comportement, Institut de Neurosciences Paris-Saclay (Neuro-PSI) CNRS UMR 9197, Université Paris Sud, Bat. 446, 91405, Orsay, France

    Men Su, Kambiz Naderi, Nathalie Samson, Serge Laroche & Sabrina Davis

  2. Institut du Cerveau et de la Moelle épinière, INSERM, CNRS, Sorbonne Universites, ICM, 75013, Paris, France

    Ihsen Youssef & Benoit Delatour

  3. Department of Medical Chemistry, University of Szeged, Dómtér 8., Szeged, 6720, Hungary

    Livia Fülöp & Zsolt Bozso

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Contributions

SD conceived and designed the research. MS, KN, NS and IY conducted the experiments. SD, BD, MS, KN and IY analysed data. IY and BD conducted all immunohistochemistry; LF and ZB produced and tested Aβ1-42 peptide. SD drafted the paper with contributions from MS and SL, and all authors read and approved the final manuscript.

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Correspondence to Sabrina Davis.

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Su, M., Naderi, K., Samson, N. et al. Mechanisms Associated with Type 2 Diabetes as a Risk Factor for Alzheimer-Related Pathology. Mol Neurobiol 56, 5815–5834 (2019). https://doi.org/10.1007/s12035-019-1475-8

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