Amyloid Prefibrillar Oligomers: The Surprising Commonalities in Their Structure and Activity

It has been proposed that a common core of pathologic pathways exists for the large family of amyloid-associated neurodegenerations, including Alzheimer's, Parkinson's, type II diabetes and Creutzfeldt-Jacob's Disease. Aggregates of the involved proteins, independently from their primary sequence, induced neuron membrane permeabilization able to trigger an abnormal Ca2+ influx leading to synaptotoxicity, resulting in reduced expression of synaptic proteins and impaired synaptic transmission. Emerging evidence is now focusing on low-molecular-weight prefibrillar oligomers (PFOs), which mimic bacterial pore-forming toxins that form well-ordered oligomeric membrane-spanning pores. At the same time, the neuron membrane composition and its chemical microenvironment seem to play a pivotal role. In fact, the brain of AD patients contains increased fractions of anionic lipids able to favor cationic influx. However, up to now the existence of a specific common structure of the toxic aggregate, and a common mechanism by which it induces neuronal damage, synaptotoxicity and impaired synaptic transmission, is still an open hypothesis. In this review, we gathered information concerning this hypothesis, focusing on the proteins linked to several amyloid diseases. We noted commonalities in their structure and membrane activity, and their ability to induce Ca2+ influx, neurotoxicity, synaptotoxicity and impaired synaptic transmission.

Automated summary

A common core of pathologic pathways has been proposed for amyloid-associated neurodegenerations, inducing neuron membrane permeabilization and abnormal Ca2+ influx. Recent studies focusing on low-molecular-weight prefibrillar oligomers suggest a potential mechanism involving membrane-spanning pores. The neuron membrane composition and chemical microenvironment also play a critical role in the process.