Prion Protein as a Toxic Acceptor of Amyloid-β Oligomers

Purro, Silvia A.; Nicoll, Andrew J.; Collinge, John

doi:10.1016/j.biopsych.2017.11.020

Cited by 70 publications

(79 citation statements)

References 122 publications

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“…Previous studies have identified Aßo as key triggers for AD pathophysiology and PrP C as a high affinity binding site required for a range of deficits in preclinical models with cultured neurons, brain slices and mice . For this reason, the ability of anti‐PrP C antibodies to abrogate AD‐related dysfunction has been investigated.…”

Section: Discussionmentioning

confidence: 99%

“…Cellular Prion Protein (PrP C ), a glycol‐phosphatidyl‐inositol‐anchored protein highly expressed in neurons, acts as a high‐affinity receptor for Aβo and is required for learning, memory, and synaptic deficits in APP/PS1 and Tg2576 mice, though not in all AD models (reviewed in). Downstream components of the Aβo‐PrP C pathway have been elucidated and successfully targeted in APP/PS1 mice, including mGluR5, Fyn kinase, and the human AD risk gene product, Pyk2 kinase .…”

Section: Introductionmentioning

confidence: 99%

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Anti‐PrP^C antibody rescues cognition and synapses in transgenic alzheimer mice

Cox

Gunther

Brody

et al. 2019

Ann Clin Transl Neurol

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Objective Amyloid‐beta oligomers (Aßo) trigger the development of Alzheimer's disease (AD) pathophysiology. Cellular prion protein (PrPC) initiates synaptic damage as a high affinity receptor for Aßo. Here, we evaluated the preclinical therapeutic efficacy of a fully human monoclonal antibody against PrPC. This AZ59 antibody selectively targets the Aβo binding site in the amino‐terminal unstructured domain of PrPC to avoid any potential risk of direct toxicity. Methods Potency of AZ59 was evaluated by binding to PrPC, blockade of Aβo interaction and interruption of Aβo signaling. AZ59 was administered to mice by weekly intraperitoneal dosing and brain antibody measured. APP/PS1 transgenic mice were treated with AZ59 and assessed by memory tests, by brain biochemistry and by histochemistry for Aß, gliosis and synaptic density. Results AZ59 binds PrPC with 100 pmol/L affinity and blocks human brain Aßo binding to PrPC, as well as prevents synaptotoxic signaling. Weekly i.p. dosing of 20 mg/kg AZ59 in a murine form achieves trough brain antibody levels greater than 10 nmol/L. Aged symptomatic APP/PS1 transgenic mice treated with AZ59 for 5–7 weeks show a full rescue of behavioral and synaptic loss phenotypes. This recovery occurs without clearance of plaque pathology or elimination of gliosis. AZ59 treatment also normalizes synaptic signaling abnormalities in transgenic brain. These benefits are dose‐dependent and persist for at least 1 month after the last dose. Interpretation Preclinical data demonstrate that systemic AZ59 therapy rescues central synapses and memory function from transgenic Alzheimer's disease pathology, supporting a disease‐modifying therapeutic potential.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Anti‐PrP^C antibody rescues cognition and synapses in transgenic alzheimer mice

Cox

Gunther

Brody

et al. 2019

Ann Clin Transl Neurol

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“…Small peptides homologous to the unstructured N‐terminal portion of PrP may be potent inhibitors of Aβ oligomer toxicity . PrPC has been proposed to mediate the toxicity of other misfolding proteins including nonmammalian protein aggregates and its role as oligomer acceptor has recently been reviewed . However, the pathological importance of these observations remains to be determined.…”

Section: Prp106‐126 and The Role Of Oligomers In Pathogenesismentioning

confidence: 99%

Review: PrP 106‐126 – 25 years after

Forloni

Chiesa

Bugiani

et al. 2019

Neuropathology Appl Neurobio

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A quarter of a century ago, we proposed an innovative approach to study the pathogenesis of prion disease, one of the most intriguing biomedical problems that remains unresolved. The synthesis of a peptide homologous to residues 106‐126 of the human prion protein (PrP106‐126), a sequence present in the PrP amyloid protein of Gerstmann–Sträussler–Scheinker syndrome patients, provided a tractable tool for investigating the mechanisms of neurotoxicity. Together with several other discoveries at the beginning of the 1990s, PrP106‐126 contributed to underpin the role of amyloid in the pathogenesis of protein‐misfolding neurodegenerative disorders. Later, the role of oligomers on one hand and of prion‐like spreading of pathology on the other further clarified mechanisms shared by different neurodegenerative conditions. Our original report on PrP106‐126 neurotoxicity also highlighted a role for programmed cell death in CNS diseases. In this review, we analyse the prion research context in which PrP106‐126 first appeared and the advances in our understanding of prion disease pathogenesis and therapeutic perspectives 25 years later.

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“…[3] Ab is derived from amyloid precursor protein by b-a nd gsecretase enzymes and is present in the CNS in nanomolar concentrations. [6] Although the precise binding mode of this interaction remains elusive,aprevious study using antibodies targeting different epitopes of PrP has demonstrated that ADDL contains multiple PrP-binding sites. [6] Although the precise binding mode of this interaction remains elusive,aprevious study using antibodies targeting different epitopes of PrP has demonstrated that ADDL contains multiple PrP-binding sites.…”

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confidence: 99%

Amyloid‐β Peptide Induces Prion Protein Amyloid Formation: Evidence for Its Widespread Amyloidogenic Effect

Honda

2018

Angew Chem Int Ed

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Transmissible spongiform encephalopathy is associated with misfolding of prion protein (PrP) into an amyloid β-rich aggregate. Previous studies have indicated that PrP interacts with Alzheimer's disease amyloid-β peptide (Aβ), but it remains elusive how this interaction impacts on the misfolding of PrP. This study presents the first in vitro evidence that Aβ induces PrP-amyloid formation at submicromolar concentrations. Interestingly, systematic mutagenesis of PrP revealed that Aβ requires no specific amino acid sequences in PrP, and induces the misfolding of other unrelated proteins (insulin and lysozyme) into amyloid fibrils in a manner analogous to PrP. This unanticipated nonspecific amyloidogenic effect of Aβ indicates that this peptide might be involved in widespread protein aggregation, regardless of the amino acid sequences of target proteins, and exacerbate the pathology of many neurodegenerative diseases.

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Prion Protein as a Toxic Acceptor of Amyloid-β Oligomers

Cited by 70 publications

References 122 publications

Anti‐PrP^C antibody rescues cognition and synapses in transgenic alzheimer mice

Anti‐PrP^C antibody rescues cognition and synapses in transgenic alzheimer mice

Review: PrP 106‐126 – 25 years after

Amyloid‐β Peptide Induces Prion Protein Amyloid Formation: Evidence for Its Widespread Amyloidogenic Effect

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Prion Protein as a Toxic Acceptor of Amyloid-β Oligomers

Cited by 70 publications

References 122 publications

Anti‐PrPC antibody rescues cognition and synapses in transgenic alzheimer mice

Anti‐PrPC antibody rescues cognition and synapses in transgenic alzheimer mice

Review: PrP 106‐126 – 25 years after

Amyloid‐β Peptide Induces Prion Protein Amyloid Formation: Evidence for Its Widespread Amyloidogenic Effect

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Anti‐PrP^C antibody rescues cognition and synapses in transgenic alzheimer mice

Anti‐PrP^C antibody rescues cognition and synapses in transgenic alzheimer mice