Abstract
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.
Highlights
Amyloid proteins are a large family of proteins with the common tendency to aggregate through a process that, triggered by a misfolding event, involves first a slow and thermodynamically unfavorable nucleation phase followed by a rapid elongation phase leading to the formation of mature fibers (MFs) [1,2]
We studied in cellular models and in mouse hippocampal slices the protective effect exerted by NAA, an enzyme able to cut the negatively charged sialic acid present in the GM1 of the neuronal membranes, from the neurotoxicity induced by salmon calcitonin (sCT) prefibrillar oligomers (PFOs)
Morton et al, found a progressive loss of presynaptic protein complexin II and synaptobrevin 2, a small vesicular transmembrane protein, both in the brains of R6/2 mice transgenic for the Huntington’s disease (HD) mutation and in the striatum of post-mortem brains of HD patients [154]. These results suggest that abnormalities observed in the expression of proteins known to be involved in the control of neurotransmitter release, including both modulators and major components of the vesicle fusion mechanism, could explain at least some of the functional abnormalities observed in HD [154]
Summary
Amyloid proteins are a large family of proteins with the common tendency to aggregate through a process that, triggered by a misfolding event, involves first a slow and thermodynamically unfavorable nucleation phase followed by a rapid elongation phase (seeding-nucleation model) leading to the formation of mature fibers (MFs) [1,2]. They highlighted commonalities and differences between distinct protein aggregates and discussed evidence supporting the hypothesis that misfolded aggregates may be transmissible by the prion principle following a “cross seeding” behavior [26] To further investigate this intriguing hypothesis of the existence of a common structure and action mechanism in the amyloid neurodegenerations, in the present review we will focus our attention on i) commonalities between structural and functional features of the toxic PFOs of amyloid proteins and models and ii) commonalities between PFOinduced effects on synaptic function and transmission, considered as the main molecular and electrophysiological mechanisms responsible for neuronal dysfunction related to cognitive impairment
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