Aβ induces its own prion protein N-terminal fragment (PrPN1)–mediated neutralization in amorphous aggregates

Béland, Maxime; Bédard, Mikaël; Tremblay, Guillaume; Lavigne, Pierre; Roucou, Xavier

doi:10.1016/j.neurobiolaging.2014.02.001

Cited by 34 publications

(37 citation statements)

References 58 publications

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“…The C1 fragment, created by α-cleavage of PrP C , lacks both the putative Aβ binding sites. Therefore, the reduced levels of hippocampal PrP C and the increased rates of PrP C α-cleavage in the cortex that have been reported in the brains of sporadic AD patients could be part of a protective response (Whitehouse et al, 2010; Beland et al, 2014). On the other hand, one study found that higher levels of PrP C in serum were correlated with poorer cognitive function in an elderly human population, although the increase in serum PrP C could be a consequence of loss of PrP C from neuronal membranes (Breitling et al, 2012).…”

Section: Prpc Functionmentioning

confidence: 99%

Physiological Functions of the Cellular Prion Protein

Castle

Gill

2017

Front. Mol. Biosci.

168

157

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The prion protein, PrPC, is a small, cell-surface glycoprotein notable primarily for its critical role in pathogenesis of the neurodegenerative disorders known as prion diseases. A hallmark of prion diseases is the conversion of PrPC into an abnormally folded isoform, which provides a template for further pathogenic conversion of PrPC, allowing disease to spread from cell to cell and, in some circumstances, to transfer to a new host. In addition to the putative neurotoxicity caused by the misfolded form(s), loss of normal PrPC function could be an integral part of the neurodegenerative processes and, consequently, significant research efforts have been directed toward determining the physiological functions of PrPC. In this review, we first summarise important aspects of the biochemistry of PrPC before moving on to address the current understanding of the various proposed functions of the protein, including details of the underlying molecular mechanisms potentially involved in these functions. Over years of study, PrPC has been associated with a wide array of different cellular processes and many interacting partners have been suggested. However, recent studies have cast doubt on the previously well-established links between PrPC and processes such as stress-protection, copper homeostasis and neuronal excitability. Instead, the functions best-supported by the current literature include regulation of myelin maintenance and of processes linked to cellular differentiation, including proliferation, adhesion, and control of cell morphology. Intriguing connections have also been made between PrPC and the modulation of circadian rhythm, glucose homeostasis, immune function and cellular iron uptake, all of which warrant further investigation.

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Section: Prpc Functionmentioning

confidence: 99%

Physiological Functions of the Cellular Prion Protein

Castle

Gill

2017

Front. Mol. Biosci.

168

157

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“…However, in its soluble form as secreted upon PrP C cleavage, N1 acted in a decoy receptor-like mode: it prevented Aβ peptide fibrillization and reduced the neurotoxicity of amyloid-β oligomers in vitro and in vivo [130]. Additionally, the rate of PrP C alpha-cleavage is increased in brain tissue from patients suffering from AD and it was proposed that alpha-cleavage represents an endogenous protective mechanism against amyloid-β toxicity in humans [131]. …”

Section: Possible Neuroprotective Roles Of Prpcmentioning

confidence: 99%

The biological function of the cellular prion protein: an update

2017

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The misfolding of the cellular prion protein (PrPC) causes fatal neurodegenerative diseases. Yet PrPC is highly conserved in mammals, suggesting that it exerts beneficial functions preventing its evolutionary elimination. Ablation of PrPC in mice results in well-defined structural and functional alterations in the peripheral nervous system. Many additional phenotypes were ascribed to the lack of PrPC, but some of these were found to arise from genetic artifacts of the underlying mouse models. Here, we revisit the proposed physiological roles of PrPC in the central and peripheral nervous systems and highlight the need for their critical reassessment using new, rigorously controlled animal models.

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“…59 We have shown that PrP C α-cleavage is increased in post-mortem human Alzheimer disease brains. 64 Thus, increased secretion of PrP C N-terminal domain may represent an endogenous compensatory mechanism aimed at interfering with Aβ-mediated toxicity.…”

Section: Prpmentioning

confidence: 99%

“…In agreement for this mechanism, PrPN1 association with Aβ causes a conformational change resulting in the formation of amorphous and insoluble aggregates that are not compatible with the amyloidogenic pathway leading to the assembly of Aβ oligomers and fibrils. 64 Another issue relates to the fate of PrPN1/PrP res or PrPN1/Aβ complexes. We have provided evidence for the presence of PrPN1/Aβ complexes in the guanidine-extractable fraction presumably representing insoluble amyloid plaques in post-mortem brain tissues of Alzheimer disease patients.…”

Section: Prpmentioning

confidence: 99%

“…We have provided evidence for the presence of PrPN1/Aβ complexes in the guanidine-extractable fraction presumably representing insoluble amyloid plaques in post-mortem brain tissues of Alzheimer disease patients. 64 Interestingly, non-identified PrP C molecules were found in Alzheimer disease extracellular plaques. 62 These plaques were mainly recognized by antibodies targeting the N-terminal moiety of PrP C , and it is tempting to speculate that PrP C molecules found in these extracellular plaques of Alzheimer disease might be PrPN1.…”

Section: Prpmentioning

confidence: 99%

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