Neuroprotective effect and potential of cellular prion protein and its cleavage products for treatment of neurodegenerative disorders part II: strategies for therapeutics development

ABSTRACT

Introduction: The cellular prion protein (PrP^C), some of its derivatives (especially PrP N-terminal N1 peptide and shed PrP), and PrP^C-containing exosomes have strong neuroprotective activities, which have been reviewed in the companion article (Part I) and are briefly summarized here.

Areas covered: We propose that elevating the extracellular levels of a protective PrP form using gene therapy and other approaches is a very promising novel avenue for prophylactic and therapeutic treatments against prion disease, Alzheimer’s disease, and several other neurodegenerative diseases. We will dissect the pros and cons of various potential PrP-based treatment options and propose a few strategies that are more likely to succeed. The cited references were obtained from extensive PubMed searches of recent literature, including peer-reviewed original articles and review articles.

Expert opinion: Concurrent knockdown of celllular PrP expression and elevation of the extracellular levels of a neuroprotective PrP N-terminal peptide via optimized gene therapy vectors is a highly promising broad-spectrum prophylactic and therapeutic strategy against several neurodegenerative diseases, including prion diseases, Alzheimer’s disease and Parkinson’s disease.

KEYWORDS:

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

Acknowledgments

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Article highlights

• The extracellular prion protein (PrP) forms, such as shed PrP, exosomal PrP and PrP N-terminal fragments (PrP-N) can inhibit and neutralize key toxic molecules and prevent toxic signaling in prion diseases (PrD), Alzheimer’s disease (AD), Parkinson’s Disease (PD) and a few other related protein misfolding neurodegenerative diseases.

• Several strategies to harness the protective powers of the extracellular PrP forms are explored, including direct infusion with a recombinant PrP form, infusion of recombinant enzymes that release the PrP form from the cell surface (ADAM10 or ADAM8 or ADAM17), peripheral infusion with PrP-rich exosomes engineered to target the brain, or increased expression of a secreted form of PrP from a gene therapy vector, or enhancing the expression/activities of an endogenous secretase or sheddase.

• Expected challenges for each strategy are discussed, including unwanted increased biological activity of the PrP form, indirect side effects of increased PrP cleavage enzyme activity, difficulty in generating the sufficient recombinant proteins or gene therapy vectors for treatment, risk of immune responses to recombinant proteins or gene therapy vector, and potential carcinogenicity of the gene therapy vector.

• The optimal strategy to increase PrP-N levels consists of a gene therapy vector that can achieve sustained high-level expression and secretion of PrP-N in the CNS after a single injection.

• Another appealing strategy is to elevate the ADAM9 activity that will activate ADAM10 to enhance both the α-cleavage of APP and the shedding of PrP^C.

• Simultaneous knockdown of cellular PrP expression and elevation of the extracellular levels of a PrP-N via optimized gene therapy vectors should be a highly promising broad-spectrum prophylactic and therapeutic strategy against several neurodegenerative diseases, including PrD, AD, and PD.

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.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

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