Synthetic peptides may suppress formation of harmful amyloid aggregates

In Alzheimer's disease, the degeneration of brain cells is linked to formation of toxic protein aggregates and deposits known as amyloid plaques. Similar processes play an important role also in type 2 diabetes. A research team has now developed “mini-proteins”, so-called peptides, which are able to bind the proteins that form amyloids and prevent their aggregation into cytotoxic amyloids.

Many cell- and neurodegenerative diseases are linked to the formation of toxic protein aggregates which cause cell death. Prominent representatives of these diseases are Alzheimer's disease and type 2 diabetes mellitus, with worldwide more than 50 million and 400 million patients, respectively. Importantly, the number of Alzheimer's and diabetes patients constantly rises, as the population becomes older. However, the two diseases remain so far incurable. Therefore, there is an urgent need for new therapeutic approaches.

Cross-interactions between amyloid-β peptide (Aβ) and islet amyloid polypeptide (IAPP), key polypeptides of Alzheimer’s disease (AD) and type 2 diabetes (T2D), have been suggested to link AD with T2D pathogenesis

Targeting the formation of harmful amyloid aggregates is a promising approach. A team has now developed novel synthetic peptides, which are able in experimental models to block toxic amyloid aggregation linked to both diseases.

The researchers show that constrained peptides designed to mimic the Aβ amyloid core (ACMs) are nanomolar cross-amyloid inhibitors of both IAPP and Aβ42 and effectively suppress reciprocal cross-seeding. Remarkably, ACMs act by co-assembling with IAPP or Aβ42 into amyloid fibril-resembling but non-toxic nanofibers and their highly ordered superstructures.

Co-assembled nanofibers exhibit various potentially beneficial features including thermolability, proteolytic degradability, and effective cellular clearance which are reminiscent of labile/reversible functional amyloids.

Previous studies showed that certain “cross-interactions” between the amyloidogenic proteins of the two diseases dramatically accelerate their amyloid aggregation process. These findings could possibly explain why people suffering from one of the two diseases might have an increased risk for the other disease as well.

The team developed synthetic peptides that could function as effective inhibitors of amyloid aggregation in both diseases. The senior author says: "The designed peptides are in fact able to bind the amyloidogenic proteins linked to both diseases and to effectively suppress both cytotoxic amyloid aggregation and amyloid cross-accelerating interactions. Remarkably, although the mixed aggregates formed by interactions of the designed peptides with the amyloidogenic proteins look very similar to harmful amyloid aggregates, they are completely devoid of cytotoxic effects. Moreover, these amyloid-resembling mixed aggregates become more efficiently taken up by the phagocytic immune cells than amyloid aggregates.”

Increasing evidence suggests that Alzheimer’s disease and type 2 diabetes are linked to each other. The senior author believes thus that the designed peptides could be valuable candidates for the development of drugs for treating both diseases.