Monoacylated Cellular Prion Proteins Reduce Amyloid-β-Induced Activation of Cytoplasmic Phospholipase A2 and Synapse Damage

Biology

Ewan West²  Craig Osborne²  William Nolan²  Clive Bate¹ 

[1] Department of Pathology and Pathogen Biology, Royal Veterinary College, Hawkshead Lane, North Mymms, Herts AL97TA, UK;

关键词: Alzheimer’s disease;    amyloid-β;    glycosylphosphatidylinositols;    prion;    synapses;    synaptophysin;   

DOI  :  10.3390/biology4020367

来源: mdpi

【 摘 要 】

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the accumulation of amyloid-β (Aβ) and the loss of synapses. Aggregation of the cellular prion protein (PrP^C) by Aβ oligomers induced synapse damage in cultured neurons. PrP^C is attached to membranes via a glycosylphosphatidylinositol (GPI) anchor, the composition of which affects protein targeting and cell signaling. Monoacylated PrP^C incorporated into neurons bound “natural Aβ”, sequestering Aβ outside lipid rafts and preventing its accumulation at synapses. The presence of monoacylated PrP^C reduced the Aβ-induced activation of cytoplasmic phospholipase A₂ (cPLA₂) and Aβ-induced synapse damage. This protective effect was stimulus specific, as treated neurons remained sensitive to α-synuclein, a protein associated with synapse damage in Parkinson’s disease. In synaptosomes, the aggregation of PrP^C by Aβ oligomers triggered the formation of a signaling complex containing the cPLA₂.a process, disrupted by monoacylated PrP^C. We propose that monoacylated PrP^C acts as a molecular sponge, binding Aβ oligomers at the neuronal perikarya without activating cPLA₂ or triggering synapse damage.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.