Journal
MOLECULAR NEUROBIOLOGY
Volume 56, Issue 8, Pages 5815-5834Publisher
SPRINGER
DOI: 10.1007/s12035-019-1475-8
Keywords
Type 2 diabetes; Alzheimer's disease; Amyloid beta; PI3K-Akt signalling; Insulin; Human junk food; CA1; Object recognition; Environment enrichment
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Funding
- Centre National de la Recherche Scientifique (CNRS, France)
- LECMA Vaincre Alzheimer, France [12702]
- Hungarian Brain Research Programme 2.0 [2017-1.2.1-NKP-2017-00002]
- Economy Development and Innovation Operative Programme [GINOP 2.3.2_15_2016_00038]
- China Scholarship Council
- LECMA funding
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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 35weeks, 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 (A beta 42) to mimic the early preclinical rise in A beta alone induced a more severe, but short-lasting deficits in memory and deregulation of proteins. Infusion of A beta on the T2D phenotype exacerbated and prolonged the memory deficits over approximately 4months, 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 A beta levels are transiently effective in the brain.
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