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Amyloid Seeding May Link Alzheimer’s, Diabetes

By : on : March 3, 2015 comments : (Comments Off on Amyloid Seeding May Link Alzheimer’s, Diabetes)

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Cross-seeding between islet and beta amyloids may link Alzheimer’s & Diabetes

by Salynn Boyles Contributing Writer

Patients with type 2 diabetes have an increased risk for developing Alzheimer’s disease, and now researchers in Sweden may have discovered the molecular link that explains the association.

The research focused on amyloidosis — the process by which misfolded amyloid proteins form insoluble fibril deposits — which occurs in a host of diseases, including type 2 diabetes and Alzheimer’s.

In transgenic mice, amyloid from the brain was found to stimulate the growth of fibrils in the pancreas, and pancreatic amyloid was also found in amyloid specific to human brain senile plaques.

“Heterologous seeding between islet amyloid polypeptide (IAPP) and amyloid-beta (A-beta) … may represent a molecular link between type 2 diabetes and Alzheimer’s disease,” researcherGunilla T. Westermark, PhD, of Uppsala University, Uppsala, Sweden, and colleagues wrote in The American Journal of Pathology, published online Feb. 17.

Molecular Interaction Links Different Amyloids

Amyloid fibrils are formed by normally soluble proteins that assemble to form insoluble, degradation-resistant fibers. Their formation is associated with disease, and each disease is characterized by a specific protein or peptide.

“Several proteins have been identified as amyloid forming in humans, and independent of protein origin, the fibrils are morphologically similar,” Westermark and colleagues wrote. “Therefore, there is a potential for structures with amyloid seeding ability to induce both homologous and heterologous fibril growth; thus, molecular interaction can constitute a link between different amyloid forms.”

To test this hypothesis, the researchers injected human IAPP transgenic mice with preformed fibrils from IAPP, proIAPP, A-beta, human proinsulin (CA), or sodium chloride (NaCl) after feeding the mice a high-fat diet for 10 months. The mice were sacrificed and amyloid-specific dye was used to analyze tissues from various organs.

The number of islets with amyloid was found to be significantly increased in the injected animals, compared with controls, with all three types of fibrils. The amyloid consisted of IAPP in all groups. No amyloid deposits were found in the spleen, kidney, liver, heart, or lungs of the animals.

“Not only the number of mice with islet amyloid was higher, but also the number of islets with amyloid was significantly increased from 2.7% and 5% in mice injected with sodium chloride and CA, respectively, to 24% in mice injected with human IAPP fibrils, and 15% in mice injected with human proIAPP or A-beta fibrils,” the researchers wrote.

“These results suggest that the local islet amyloid can be seeded by circulating amyloid seeds, and the efficiency depends on structural similarity between seed and amyloid precursor.”

Cross-Seeding May Initiate Amylin Formation

Following the mouse experiments, the researchers used proximity ligation assay to study IAPP and A-beta colonization in islet amyloid in tissue from four type 2 diabetic patients and A-beta deposits in the brain tissue from four patients with Alzheimer’s disease.

“A-beta reactivity was not detected in islet amyloid although islet beta cells express A-betaPP and convertases necessary for A-beta production,” the researchers wrote.

However, IAPP and proIAPP were detected in cerebral and vascular A-beta deposits, and the presence of proximity ligation signal at both locations showed that the peptides were <40 nm apart, the researchers wrote.

IAPP was found in brain extracts from Alzheimer’s disease patients, but significantly less was found in samples from the brains of four non-Alzheimer’s control patients.

“From our studies of patient material, we have found that islet IAPP amyloid does not recruit A-beta, but that cerebral A-beta amyloid contains IAPP,” the researchers wrote. “Seeding of IAPP with preformed fibrils of IAPP shows that homologous seeding is more effective than the heterologous seeding of IAPP with A-beta.”

While much is known about the formation of amyloid fibrils in vitro, the researchers noted that how different forms of amyloid proteins interact and how amyloid is initiated in vivo has not been well understood.

“Cross-seeding by other amyloid aggregates or perhaps by other types of aggregates offers one possible mechanism for initiation of amyloid formation,” they wrote. “Interactions between amyloid and other aggregation-prone proteins may be of great importance in the development of protein-misfolding diseases.”

This research was funded by the Swedish Research Council, the Swedish Diabetes Association, and the Family Ernfors Fund.

The researchers disclosed no relevant relationships with industry.



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