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Sci Rep. 2016 Jul 12;6:29396. doi: 10.1038/srep29396.

Chronic hyperglycemia induced via the heterozygous knockout of Pdx1 worsens neuropathological lesion in an Alzheimer mouse model.

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College of Life and Health Sciences, Northeastern University, Shenyang, 110819, P. R. China.
Basic Medicine Combined with Chinese Traditional Medicine and Western Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang 110847, P. R. China.
Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, 110001, P. R. China.


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-β (Aβ) 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 Aβ precursor proteins and result in increased Aβ generation and decreased Aβ 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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