Abstract
The role for cellular prion protein PrPc in β-amyloid (Aβ) oligomer-induced synaptic impairment is a topic of great interest and some controversy. In this issue of EMBO Molecular Medicine Aguzzi and co-workers explore the contribution of PrPc to deficient long term potentiation (LTP) and soluble Aβ levels in an Alzheimer's disease mouse model and show that the role of prions in Aβ related toxicity is far from ‘black and white’ suggesting complex interpretations of the data available thus far.
Highlights
Pathogenic amyloid formation is characteristic of several neurodegenerative disorders including Alzheimer’s and Parkinson’s disease, transmissible spongiform encephalopathies and others (Aguzzi & O’Connor, 2010)
Prion protein (PrP) was identified in an unbiased screening for receptors that could bind Ab42 oligomers prepared according to a particular protocol to yield Ab-derived diffusible ligands (ADDL) (Lambert et al, 1998)
These oligomers failed to impair long term potentiation (LTP) in mouse hippocampal slices lacking PrP (Lauren et al, 2009) and the same authors have recently demonstrated that in an Alzheimer’s disease (AD) transgenic mouse model (APPswe/Psen1DE9) characterized by amyloid plaques formation and learning and memory deficits, deletion of the endogenous PrP gene prevented the development of the functional deficits despite unchanged levels of Ab generation and Ab deposition in their brains (Gimbel et al, 2010)
Summary
Pathogenic amyloid formation is characteristic of several neurodegenerative disorders including Alzheimer’s and Parkinson’s disease, transmissible spongiform encephalopathies and others (Aguzzi & O’Connor, 2010). Recent insights suggest that small oligomeric assemblies of Ab, in contrast to monomeric and fibrillar species, are toxic for neuronal synapses, but the molecular targets of these assemblies and the mechanism of toxicity remain very controversial topics (Ashe & Zahs, 2010, see supplemental data there).
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