These diseases are caused by proteins that aggregate: Aβ in Alzheimer’s disease, α-synuclein in Parkinson’s disease, amylin in type II diabetes, and others in amyotrophic lateral sclerosis (ALS) or Creutzfeldt-Jakob disease.
These proteins belong to the class of intrinsically disordered proteins (IDPs), which lack a stable 3D structure, making them difficult to target. IDPs account for 50% of human proteins. They can assemble in different ways, forming oligomers, fibrils and amyloid plaques. Among these structures, oligomers are the most toxic forms and the earliest to appear in the course of pathogenesis.
These oligomers, either preformed or assembled within the membrane from inserted monomers, form pores in it. In both cases, pore formation depends on an initial interaction with gangliosides, lipids concentrated in specific domains of the plasma membrane known as “rafts”, as shown in the video below. These pores, known as “amyloid pores”, are permeable to calcium. Ca2+ ions then accumulate inside the cell, triggering a toxic cascade that leads to cell death.
This mechanism is common to many diseases involving IDPs. As gangliosides are a preferred target of the IDPs involved in amyloid pore formation, AmyPore is the first biotech company to target gangliosides.
Drawing on their expertise and knowledge of cell membrane composition, our researchers have decoded the biological code that controls the formation of these amyloid pores. This enabled them to model, at the atomic scale, the common and complete process of amyloid pore formation by the Aβ protein, in Alzheimer’s disease, and α-synuclein, in Parkinson’s disease.
The massive and sustained influx of Ca2+ ions triggers a neurotoxic cascade that includes the classic hallmarks of these diseases: Tau protein hyperphosphorylation and mitochondrial oxidative stress. Ultimately, the cells undergo major functional disruption, leading to their degeneration and then to cell death.
AmyPore’s researchers discovered this key step, shared by both diseases. In many patients, Aβ and α-synuclein pathologies coexist: targeting their common mechanism makes it possible to act on both at once.
Today, AmyPore is the only company whose molecule prevents the formation of amyloid pores: AmyP53, its first adaptive peptide with a revolutionary mechanism of action, a true game changer.
