A beta induces its own prion protein N-terminal fragment (PrPN1)-mediated neutralization in amorphous aggregates

作者：Beland Maxime; Bedard Mikael; Tremblay Guillaume; Lavigne Pierre; Roucou Xavier^*

来源：Neurobiology of Aging, 2014, 35(7): 1537-1548.

DOI：10.1016/j.neurobiolaging.2014.02.001

• Alzheimer
• alpha-Cleavage
• PrPN1
• A beta
• Amorphous aggregates
• Diffuse plaques
• Prion
• Neuroprotection
• Fibrillization

Plasma membrane cellular prion protein (PrPC) is a high-affinity receptor for toxic soluble amyloid-beta (A beta) oligomers that mediates synaptic dysfunction. Secreted forms of PrPC resulting from PrPC alpha-cleavage (PrPN1) or shedding (shed PrPC) display neuroprotective activity in neuronal cultures and in mouse models of A beta-induced neuronal dysfunction. In vitro, recombinant PrPN1 and PrP inhibit A beta fibrillization. However, the mechanism by which PrPN1 and shed PrPC neutralize A beta oligomers is unclear, and evidence of such neuroprotective activity in Alzheimer%26apos;s disease (AD) patients is lacking. Here, we show that PrPN1 association with A beta causes a conformational change resulting in the formation of amorphous and insoluble aggregates that are not compatible with the assembly of A beta s. Using postmortem brain tissues of AD patients, we were able to coimmunoprecipitate A beta with PrPC molecules and observed a coaggregation of A beta and PrPN1 in the guanidine-extractable fraction presumably representing insoluble amyloid plaques. Furthermore, PrPC alpha-cleavage is increased in AD brains, and we noticed a significant positive correlation between the levels of alpha-cleavage and of guanidine-extractable A beta. These data strongly support the hypothesis that PrPC alpha-cleavage is an endogenous neuroprotective mechanism in AD and support the development of PrPC-derived peptides as therapeutic molecules for AD.

• 出版日期2014-7