Prion protein and Alzheimer disease - PubMed (original) (raw)

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Prion protein and Alzheimer disease

Katherine A B Kellett et al. Prion. 2009 Oct-Dec.

Abstract

Alzheimer and prion diseases are neurodegenerative disorders characterised by the abnormal processing of amyloid-beta (Abeta) peptide and prion protein (PrP(C)), respectively. Recent evidence indicates that PrP(C) may play a critical role in the pathogenesis of Alzheimer disease. PrP(C) interacts with and inhibits the beta-secretase BACE1, the rate-limiting enzyme in the production of Abeta. More recently PrP(C) was identified as a receptor for Abeta oligomers and the expression of PrP(C) appears to be controlled by the amyloid intracellular domain (AICD). Here we review these observations and propose a feedback loop in the normal brain where PrP(C) exerts an inhibitory effect on BACE1 to decrease both Abeta and AICD production. In turn, the AICD upregulates PrP(C) expression, thus maintaining the inhibitory effect of PrP(C) on BACE1. In Alzheimer disease, this feedback loop is disrupted, and the increased level of Abeta oligomers bind to PrP(C) and prevent it from regulating BACE1 activity.

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Figures

Figure 1

Figure 1

Proteolytic processing of APP. The amyloidogenic pathway involves the sequential cleavage of APP first by BACE1, producing sAPPβ and C99, and then by γ-secretase to release the amyloidogenic Aβ and the AICD. In the non-amyloidogenic pathway, α-secretase cleaves within the Aβ fragment, preventing the formation of Aβ peptides.

Figure 2

Figure 2

A model for the regulation of APP processing by PrPC. (A) Aβ levels are kept in balance under physiological conditions via inhibition of BACE1 by PrPC and regulation of PrPC levels via AICD. (B) In AD, Aβ levels are increased as a result of increased production and/or decreased degradation and clearance resulting in the increased formation of Aβ-oligomers which are toxic via their interaction with PrPC. The binding of the Aβ-oligomers to PrPC may disrupt its regulation of BACE1, thereby further increasing APP processing and Aβ levels.

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