Neuroprotective effect and potential of cellular prion protein and its cleavage products for treatment of neurodegenerative disorders part I. a literature review

ABSTRACT

Introduction

The cellular prion protein (PrP^C) is well known for its pathogenic roles in prion diseases, several other neurodegenerative diseases (such as Alzheimer’s disease), and multiple types of cancer, but the beneficial aspects of PrP^C and its cleavage products received much less attention.

Areas covered

Here the authors will systematically review the literatures on the negative as well as protective aspects of PrP^C and its derivatives (especially PrP N-terminal N1 peptide and shed PrP). The authors will dissect the current findings on N1 and shed PrP, including evidence for their neuroprotective effects, the categories of PrP^C cleavage, and numerous cleavage enzymes involved. The authors will also discuss the protective effects and therapeutic potentials of PrP^C-rich exosomes. The cited articles were obtained from extensive PubMed searches of recent literature, including peer-reviewed original articles and review articles.

Expert Opinion

PrP and its N-terminal fragments have strong neuroprotective activities that should be explored for therapeutics and prophylactics development against prion disease, Alzheimer’s disease and a few other neurodegenerative diseases. The strategies to develop PrP-based therapeutics and prophylactics for these neurodegenerative diseases will be discussed in a companion article (Part II).

KEYWORDS:

• Alpha-cleavage
• ADAM
• Aβ and other toxic oligomers
• Alzheimer’s disease
• neurodegenerative diseases
• N1 peptide
• neuroprotection
• prion protein
• shedding
• therapeutics

Acknowledgments

The figures were created with BioRender.com.

Article highlights

• The full length cellular prion protein (PrP^C) has diverse biological roles, such as neuronal survival, stress protection, neuronal excitation, peripheral myelin maintenance, and cellular proliferation and differentiation, yet PrP-null animals are largely normal.

• PrP^C is essential for prion diseases and serves as a key common receptor for a few toxic protein oligomers in Alzheimer’s disease (AD) and a few other common neurodegenerative diseases involving Tau or α-synuclein (αSyn).

• PrP^C can undergo various cleavages under physiological and pathological conditions, some of which have been shown to be protective, most notably α-cleavage and shedding.

• Extracellular forms of PrP such as shed full-length PrP, exosomal full-length PrP, the N1 peptide released by PrP^C α-cleavage from cell surface (PrP-N), or recombinant PrP forms have been shown to be protective against toxic stressors.

• The N1 peptide derived from α-cleavage of cell surface PrP and recombinant N1 can protect against the toxicity of Aβ oligomers by inhibiting Aβ oligomer formation, hindering toxic signaling, and promoting oligomer aggregation into larger fibrils that are less toxic.

• Knocking down PrP^C expression while elevating the extracellular level of the PrP N-terminal peptide should have excellent prophylactic and therapeutic potential against several neurodegenerative diseases including PrD and AD, which will be explored in depth in the companion paper [171].

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was partially supported by NIH R01 NS109532 and a research grant from CJD Foundation.