Neuroinflammation and neurologic deficits in diabetes linked to brain accumulation of amylin

Molecular Neurodegeneration

Florin Despa²  Linda J Van Eldik³  Kathryn E Saatman⁵  Xinmin Simon Xie⁶  Conrado Pascual⁶  Jennifer M Brelsfoard¹  Adam B Bachstetter⁴  Savita Sharma²  Sarah Srodulski² 

[1] Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY, USA;Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA;Department of Anatomy and Neurobiology, University of Kentucky, Lexington, KY, USA;Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA;Department of Physiology, University of Kentucky, Lexington, KY, USA;AfaSci Research Laboratories, AfaSci, Inc., Redwood City, CA, USA

关键词: Behavior;    Inflammation;    Insulin Resistance;    Pre-diabetes;    Amylin;    Alzheimer’s Disease;    Diabetes;   

Others  :  1138752
DOI  :  10.1186/1750-1326-9-30

 received in 2014-06-10, accepted in 2014-08-18,  发布年份 2014

【 摘 要 】

Background

We recently found that brain tissue from patients with type-2 diabetes (T2D) and cognitive impairment contains deposits of amylin, an amyloidogenic hormone synthesized and co-secreted with insulin by pancreatic β-cells. Amylin deposition is promoted by chronic hypersecretion of amylin (hyperamylinemia), which is common in humans with obesity or pre-diabetic insulin resistance. Human amylin oligomerizes quickly when oversecreted, which is toxic, induces inflammation in pancreatic islets and contributes to the development of T2D. Here, we tested the hypothesis that accumulation of oligomerized amylin affects brain function.

Methods

In contrast to amylin from humans, rodent amylin is neither amyloidogenic nor cytotoxic. We exploited this fact by comparing rats overexpressing human amylin in the pancreas (HIP rats) with their littermate rats which express only wild-type (WT) non-amyloidogenic rodent amylin. Cage activity, rotarod and novel object recognition tests were performed on animals nine months of age or older. Amylin deposition in the brain was documented by immunohistochemistry, and western blot. We also measured neuroinflammation by immunohistochemistry, quantitative real-time PCR and cytokine protein levels.

Results

Compared to WT rats, HIP rats show i) reduced exploratory drive, ii) impaired recognition memory and iii) no ability to improve the performance on the rotarod. The development of neurological deficits is associated with amylin accumulation in the brain. The level of oligomerized amylin in supernatant fractions and pellets from brain homogenates is almost double in HIP rats compared with WT littermates (P < 0.05). Large amylin deposits (>50 μm diameter) were also occasionally seen in HIP rat brains. Accumulation of oligomerized amylin alters the brain structure at the molecular level. Immunohistochemistry analysis with an ED1 antibody indicates possible activated microglia/macrophages which are clustering in areas positive for amylin infiltration. Multiple inflammatory markers are expressed in HIP rat brains as opposed to WT rats, confirming that amylin deposition in the brain induces a neuroinflammatory response.

Conclusions

Hyperamylinemia promotes accumulation of oligomerized amylin in the brain leading to neurological deficits through an oligomerized amylin-mediated inflammatory response. Additional studies are needed to determine whether brain amylin accumulation may predispose to diabetic brain injury and cognitive decline.

【 授权许可】

   
2014 Srodulski et al.; licensee BioMed Central Ltd.

【 图 表 】

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