Journal
SCIENTIFIC REPORTS
Volume 6, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/srep29396
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Funding
- National Grand Fundamental Research 973 Program of China [2012CB722405]
- Natural Science Foundation of China [31371091, 81170775, 81301102]
- Basic Scientific Research Fund of Northeastern University [N130120002, N142004003, N142005001, N152006001]
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Compelling evidence has indicated that dysregulated glucose metabolism links Alzheimer's disease (AD) and diabetes mellitus (DM) via glucose metabolic products. Nevertheless, because of the lack of appropriate animal models, whether chronic hyperglycemia worsens AD pathologies in vivo remains to be confirmed. Here, we crossed diabetic mice (Pdx1(+/-) mice) with Alzheimer mice (APP/PS1 transgenic mice) to generate Pdx1(+/-)/APP/PS1. We identified robust increases in tau phosphorylation, the loss of the synaptic spine protein, amyloid-beta (A beta) deposition and plaque formation associated with increased microglial and astrocyte activation proliferation, which lead to exacerbated memory and cognition deficits. More importantly, we also observed increased glucose intolerance accompanied by Pdx1 reduction, the formation of advanced glycation end-products (AGEs), and the activation of the receptor for AGEs (RAGE) signaling pathways during AD progression; these changes are thought to contribute to the processing of A beta precursor proteins and result in increased A beta generation and decreased A beta degradation. Protein glycation, increased oxidative stress and inflammation via hyperglycemia are the primary mechanisms involved in the pathophysiology of AD. These results indicate the pathological relationship between these diseases and provide novel insights suggesting that glycemic control may be beneficial for decreasing the incidence of AD in diabetic patients and delaying AD progression.
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