Alzheimer's disease and prion protein

Abstract

Alzheimer's disease (AD) is a devastating neurodegenerative disease with progressive loss of memory and cognitive function, pathologically hallmarked by aggregates of the amyloid-beta (Aβ) peptide and hyperphosphorylated tau in the brain. Aggregation of Aβ under the form of amyloid fibrils has long been considered central to the pathogenesis of AD. However, recent evidence has indicated that soluble Aβ oligomers, rather than insoluble fibrils, are the main neurotoxic species in AD. The cellular prion protein (PrP(C)) has newly been identified as a cell surface receptor for Aβ oligomers. PrP(C) is a cell surface glycoprotein that plays a key role in the propagation of prions, proteinaceous infectious agents that replicate by imposing their abnormal conformation to PrP(C) molecules. In AD, PrP(C) acts to transduce the neurotoxic signals arising from Aβ oligomers, leading to synaptic failure and cognitive impairment. Interestingly, accumulating evidence has also shown that aggregated Aβ or tau possesses prion-like activity, a property that would allow them to spread throughout the brain. In this article, we review recent findings regarding the function of PrP(C) and its role in AD, and discuss potential therapeutic implications of PrP(C)-based approaches in the treatment of AD.

Keywords: Fyn kinase; N1 fragment; PRNP gene; long-term potentiation (LTP); protein misfolding.

Figure 1.

Scheme of PrP^C primary structure. The N-terminal part includes (from left to right): a signal peptide (SP, residues 1–22) (removed during PrP biosynthesis in the endoplasmic reticulum), a polybasic region (residues 23–27, green), five histidine-containing octapeptide repeats (residues 51–90, gray) (bind Cu²⁺ and other bivalent metal ions), a central region (CR) (residues 95–111, cyan, positively charged), and a hydrophobic domain (HD, residues 111–130, highly conserved region). The C-terminal part includes (from left to right): two short β-strands (residues 127–129, yellow; and 166–168, purple), three α-helices (residues 143–152, blue; 171–191, orange; and 199–221, red), and a C-terminal peptide (residues 231–254, black), which is removed during biosynthesis, followed by covalent attachment of a glycosylphosphatidylinositol (GPI) anchor, which attaches the protein to the outer leaflet of the plasma membrane. PrP^C also contains two N-linked oligosaccharide chains (at Asn-180 and Asn-196, black lollipops) and a disulfide bond between residues 178 and 231 (indicated by a dashed line). Residues correspond to the mouse sequence. This figure is adapted from Biasini et al. Trends in Neurosciences (2012) with permission.

Figure 2.

Therapeutic development strategies for AD (The ‘PrP^C axis’). The green color portion of PrP^C indicates the protective function of PrP^C (left-hand side), and the red color portion of PrP^C indicates PrP^C as the receptor of Aβ oligomers (righthand side) to mediate the Aβ toxicity. The left-hand side of the figure indicates therapeutic strategies by enhancing the normal function of PrP^C (enhancing the inhibitory effect on BACE1, which reduces Aβ production, and enhancing the α-cleavage, which increases production of the protective N1 fragment of PrP^C). The right-hand side of the figure indicates therapeutic strategies by targeting the Aβ oligomer/PrP^C-mediated toxic signaling pathway, which encompass measures to inhibit Aβ oligomerization, Aβ prion-like activity, interaction of Aβ oligomers with PrP^C, Aβ oligomer/PrP^C-mediated disinhibition of BACE1, intermediate mediators (such as caveolin-1 and NCAM), Fyn kinase, and prion-like activity of hyperphosphorylated Tau. (Abbreviations: Aβo: Aβ oligomers; N1: N1 fragment of PrP^C; p-Tau: hyperphosphorylated Tau.)