Amyloid-β42 Interacts Mainly with Insoluble Prion Protein in the Alzheimer Brain

Abstract

The prion protein (PrP) is best known for its association with prion diseases. However, a controversial new role for PrP in Alzheimer disease (AD) has recently emerged. In vitro studies and mouse models of AD suggest that PrP may be involved in AD pathogenesis through a highly specific interaction with amyloid-␤ (A␤42) oligomers. Immobilized recombinant human PrP (huPrP) also exhibited high affinity and specificity for A␤42 oligomers. Here we report the novel finding that aggregated forms of huPrP and A␤42 are co-purified from AD brain extracts. Moreover, an anti-PrP antibody and an agent that specifically binds to insoluble PrP (iPrP) co-precipitate insoluble A␤ from human AD brain. Finally, using peptide membrane arrays of 99 13-mer peptides that span the entire sequence of mature huPrP, two distinct types of A␤ binding sites on huPrP are identified in vitro. One specifically binds to A␤42 and the other binds to both A␤42 and A␤40. Notably, A␤42-specific binding sites are localized predominantly in the octapeptide repeat region, whereas sites that bind both A␤40 and A␤42 are mainly in the extreme N-terminal or C-terminal domains of PrP. Our study suggests that iPrP is the major PrP species that interacts with insoluble A␤42 in vivo. Although this work indicated the interaction of A␤42 with huPrP in the AD brain, the pathophysiological relevance of the iPrP/A␤42 interaction remains to be established. Alzheimer disease (AD)2 is the leading cause of dementia in the elderly and the most common neurodegenerative disorder. The underlying pathology in AD seems to be associated with the accumulation of soluble and insoluble aggregated species of the amyloid-␤ (A␤) peptide in the brain (1). However, the mechanisms underlying A␤ deposition and neurotoxicity remain poorly understood. The cellular prion protein (PrP C ) is a glycoprotein highly expressed in the brain, and best known for its association with prion diseases. These are unique neurodegenerative disorders with an infectious, sporadic or genetic etiology, and which are characterized by deposition of misfolded, pathological PrP (PrP Sc ) in the brain (2). Interestingly, a recent interpretation of early and newer observations suggests that PrP C may play a role in the pathogenesis of AD (3). Epidemiological studies suggest that the Met/Val polymorphism at residue 129 in PrP modulates the number of A␤ deposits (4). Also, pathological evidence indicates that PrP deposits often accompany A␤ plaques in AD (5-7). Moreover, transgenic mice expressing mutant amyloid precursor protein (APP) and overexpressing hamster PrP C present an exacerbated A␤ plaque burden (8). The circumstantial evidence of an association between PrP and A␤ was greatly strengthened by the recent finding that PrP was the protein that most strongly supported the binding of cells to soluble A␤42 oligomers in a screen of 225,000 murine clones (9). The authors also showed that although A␤42 oligomers suppressed long-term potentiation (LTP) in CA1 hippocampal neurons in mouse brain slices, LTP inhibitio...

Therapeutic Molecules and Endogenous Ligands Regulate the Interaction between Brain Cellular Prion Protein (PrPC) and Metabotropic Glutamate Receptor 5 (mGluR5)

“…Recent progress in the field has improved our understanding of the mechanisms by which A␤o interacts with synapses and triggers synaptotoxicity. Cellular prion protein (PrP C ) has been identified as high-affinity cell surface receptor for A␤o (14), which has been confirmed both in vivo and in vitro (15)(16)(17). Numerous AD-related deficits are dependent on the presence of PrP C , such as A␤o-triggered synaptic dysfunction, dendritic spine and synapse loss, serotonin axon degeneration, epileptiform discharges, spatial learning and memory impairment, and the reduced survival of APP/PS1 transgenic mice (1, 14, 18 -22).…”

“…Numerous AD-related deficits are dependent on the presence of PrP C , such as A␤o-triggered synaptic dysfunction, dendritic spine and synapse loss, serotonin axon degeneration, epileptiform discharges, spatial learning and memory impairment, and the reduced survival of APP/PS1 transgenic mice (1, 14, 18 -22). A␤o-PrP C complexes are extractable from human AD brains, and human AD brain-derived A␤o inhibits synaptic function in a PrP C -dependent manner (15,19,23,24). Furthermore, blockade of the interaction between A␤o and PrP C , which has been mapped to regions 23-27 and 95-110 in PrP C , prevents A␤o-induced inhibition of synaptic plasticity (14,17).…”

Prion-Protein-interacting Amyloid-β Oligomers of High Molecular Weight Are Tightly Correlated with Memory Impairment in Multiple Alzheimer Mouse Models

“…For example, experiments with a range of models have shown that A␤o toxicity is critically dependent on cellular prion protein (PrP C ), a cell surface glycoprotein acting as a high affinity receptor with high selectivity for A␤o (21)(22)(23)(24)(25)(26)(27)(28). Interaction between A␤o and PrP C is essential for development of an array of AD features, including activation of certain signaling cascades, synaptotoxicity, inhibition of long term potentiation, memory impairment, and decreased survival in mice (25,(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43).…”

Cross-interactions between the Alzheimer Disease Amyloid-β Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis

“…PrP seems to affect the biological activity of A␤42 through direct interactions, and aggregated forms of human PrP and A␤42 have been co-purified from AD brain material (10). Cellular PrP has been identified as a high-affinity receptor for A␤ oligomers.…”