Abstract
BackgroundWe 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.MethodsIn 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.ResultsCompared 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.ConclusionsHyperamylinemia 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.
Highlights
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
We documented the specificity of human amylin RNA expression in the pancreas in Human islet amyloid polypeptide (HIP) rats by quantitative real-time PCR
The results indicate that a “human” hyperamylinemia promotes accumulation of oligomerized amylin in the brain, which may trigger an inflammatory response leading to neurological deficits (Figures 2 and 3)
Summary
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. We have recently [5] shown that brain tissue from patients with T2D and cerebrovascular dementia or Alzheimer’s disease (AD) contains significant accumulation of the pancreatic hormone amylin (islet amyloid polypeptide). We report effects of amylin accumulation on brain function in an animal model. A 37 amino acid peptide with amyloidogenic properties, is synthesized and co-secreted with insulin by pancreatic β-cells [6] and plays a complex role in modulating peripheral energy balance. Some of the metabolic effects exerted by amylin are opposite those of insulin [7,8,9,10]. The authors [19] suggest that the amylin hormone mediates the translocation of β-amyloid (Aβ) peptide from the brain
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