Common molecular mechanism of amyloid pore formation by Alzheimer’s β-amyloid peptide and α-synuclein

Abstract

Calcium-permeable pores formed by small oligomers of amyloid proteins are the primary pathologic species in Alzheimer’s and Parkinson’s diseases. However, the molecular mechanisms underlying the assembly of these toxic oligomers in the plasma membrane of brain cells remain unclear. Here we have analyzed and compared the pore-forming capability of a large panel of amyloid proteins including wild-type, variant and truncated forms, as well as synthetic peptides derived from specific domains of Aβ1-42 and α-synuclein. We show that amyloid pore formation involves two membrane lipids, ganglioside and cholesterol, that physically interact with amyloid proteins through specific structural motifs. Mutation or deletion of these motifs abolished pore formation. Moreover, α-synuclein (Parkinson) and Aβ peptide (Alzheimer) did no longer form Ca2+-permeable pores in presence of drugs that target either cholesterol or ganglioside or both membrane lipids. These results indicate that gangliosides and cholesterol cooperate to favor the formation of amyloid pores through a common molecular mechanism that can be jammed at two different steps, suggesting the possibility of a universal therapeutic approach for neurodegenerative diseases. Finally we present the first successful evaluation of such a new therapeutic approach (coined “membrane therapy”) targeting amyloid pores formed by Aβ1-42 and α-synuclein.

Soluble Oligomers Require a Ganglioside to Trigger Neuronal Calcium Overload

“…This view agrees with our recent data showing a reduced mobility of GM1 molecules in GM1-enriched neuronal cells by Single Molecule Tracking (SMT) experiments [8]. Our data also agree with several reports indicating that the cholesterol content affects membrane physical features such as fluidity and GM1 clustering, hindering both aggregate recruitment at the cell membrane and membrane permeabilization [63,65]. Overall, our results indicate that age-dependent clustering of membrane GM1 in neurons, a well-known alteration in the AD brain [3], can represent a risk for neurodegeneration in elderly people as a consequence of an increased ability of the lipid components of the bilayers to recruit membranepermeabilizing oligomers without any involvement of specific receptors.…”

“…The affinity of protein aggregates for membrane GM1 was suggested to involve the negative charge of the sialic acid [63,64]. Our results agree with these considerations; in fact, we showed that A␤ 42 oligomers display an increased tendency to interact with SUVs as far as GM1 abundance is raised, supporting the idea that aggregate binding is not only driven by the presence of membrane protein targets [64].…”

High-Resolution Structures of the Amyloid-β 1–42 Dimers from the Comparison of Four Atomistic Force Fields

“…Knowledge of this structural ensemble is interesting not only to design inhibitors, 72,73 but also to understand the interactions with many cellular partners in early stage Alzheimer’s disease. 4,74–77 …”

Influence of the Aqueous Environment on Protein Structure—A Plausible Hypothesis Concerning the Mechanism of Amyloidogenesis

“…The topic of amyloidogenesis has been the subject of many scientific endeavors and a great variety of papers have been published, approaching the problem from all possible angles: diagnostics [63][64][65][66], therapeutic [67][68][69][70][71][72][73][74][75][76][77][78][79][80][81] and structural/molecular [82][83][84][85]. Our publication does not, however, discuss amyloidogenesis as such, but rather the molecular processes which lead to the formation of fibrillary aggregates commonly referred to as amyloids.…”