Amylin deposition in the brain: A second amyloid in Alzheimer disease?

Abstract

Objectives Hyperamylinemia, a common pancreatic disorder in obese and insulin resistant patients, is known to cause amylin oligmerization and cytotoxicity in pancreatic islets leading to β-cell mass depletion and development of type-2 diabetes. Recent data revealed that hyperamylinemia also affects the vascular system, heart and kidneys. We, therefore, hypothesized that oligomerized amylin might accumulate in cerebrovascular system and brain parenchyma of diabetic patients. Methods Amylin accumulation in the brain of diabetic patients with vascular dementia or Alzheimer’s disease (AD), non-diabetic patients with AD, and age-matched healthy controls was assessed by quantitative real-time PCR, immunohistochemistry, western blot and ELISA. Results Amylin oligomers and plaques were identified in the temporal lobe gray matter from diabetic patients, but not controls. In addition, extensive amylin deposition was found in blood vessels and perivascular spaces. Intriguingly, amylin deposition was also detected in blood vessels and brain parenchyma of patients with late-onset AD without clinically apparent diabetes. Mixed amylin and Aβ deposits were occasionally observed. However, amylin accumulation leads to amyloid formation independent of Aβ deposition. Tissues infiltrated by amylin show increased interstitial space, vacuolation, spongiform change, and capillaries bended at amylin accumulation sites. Unlike the pancreas, there was no evidence of amylin synthesis in the brain. Interpretations Metabolic disorders and aging promote accumulation of amylin amyloid in cerebrovascular system and gray matter altering microvasculature and tissue structure. Amylin amyloid formation in the wall of cerebral blood vessels may also induce failure of elimination of Aβ from the brain, thus contributing to the etiology of AD.

Cross-talk between amyloidogenic proteins in type-2 diabetes and Parkinson’s disease

“…Finally, our findings provide a simple justification for why T2D is a risk factor for PD (as IAPP amyloid seeds, present in T2D, trigger aS amyloid formation), whereas patients with PD are not prone to getting T2D (aS amyloid seeds, present in PD, inhibit IAPP amyloid formation) (36,37). Because aS and IAPP may come in contact with each other both in pancreatic β-cells (33) and in various brain cells (48)(49)(50), and amyloidogenic assemblies may spread from cell to cell (51), in vivo studies are desired to reveal the biological consequences of the cross-reactivity detected here.…”

“…Despite these facts, putative cross-talk between aS and processed and/or unprocessed IAPP has not been addressed previously. The importance of possible cross-reactivity between these proteins is also underscored by recent reports demonstrating that IAPP is present in brain cells and may form amyloidogenic deposits there, although the IAPP peptide appeared to be synthesized elsewhere (41,(48)(49)(50).…”

Prion-Like Protein Aggregates and Type 2 Diabetes

“…IAPP deposition has been reported in the gray matter of the temporal lobe in the brains of T2D patients (Jackson et al 2013). IAPP deposits were also found in both blood vessels and perivascular spaces, suggesting an influx from peripheral circulation (Jackson et al 2013). …”

“…Although the amount of IAPP injected in this study is substantially higher than the physiological level of IAPP found in the blood, these results strongly suggest that blood can be an effective route for spreading of IAPP aggregates from islet to islet. Furthermore, IAPP deposits positively stained with Congo red were found in blood vessels of the brain from individuals affected by T2D, suggesting that IAPP aggregates might be present in the circulation (Jackson et al 2013). It is generally believed that islets are highly innervated by parasympathetic, sympathetic, and sensory projections (Ahren 2000).…”

“…However, epidemiological studies have shown that T2D patients exhibit an increased risk of developing AD compared with age-matched nondiabetic individuals (Biessels et al 2006). IAPP deposition has been reported in the gray matter of the temporal lobe in the brains of T2D patients (Jackson et al 2013). IAPP deposits were also found in both blood vessels and perivascular spaces, suggesting an influx from peripheral circulation (Jackson et al 2013).…”