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An ancient conserved role for prion protein in learning and memory.
- Source :
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Biology open [Biol Open] 2018 Jan 22; Vol. 7 (1). Date of Electronic Publication: 2018 Jan 22. - Publication Year :
- 2018
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Abstract
- The misfolding of cellular prion protein (PrP <superscript>C</superscript> ) to form PrP Scrapie (PrP <superscript>Sc</superscript> ) is an exemplar of toxic gain-of-function mechanisms inducing propagated protein misfolding and progressive devastating neurodegeneration. Despite this, PrP <superscript>C</superscript> function in the brain is also reduced and subverted during prion disease progression; thus understanding the normal function of PrP <superscript>C</superscript> in healthy brains is key. Disrupting PrP <superscript>C</superscript> in mice has led to a myriad of controversial functions that sometimes map onto disease symptoms, including a proposed role in memory or learning. Intriguingly, PrP <superscript>C</superscript> interaction with amyloid beta (Aβ) oligomers at synapses has also linked its function to Alzheimer's disease and dementia in recent years. We set out to test the involvement of PrP <superscript>C</superscript> in memory using a disparate animal model, the zebrafish. Here we document an age-dependent memory decline in prp2 <superscript>-/-</superscript> zebrafish, pointing to a conserved and ancient role of PrP <superscript>C</superscript> in memory. Specifically, we found that aged (3-year-old) prp2 <superscript>-/-</superscript> fish performed poorly in an object recognition task relative to age-matched prp2 <superscript>+/+</superscript> fish or 1-year-old prp2 <superscript>-/-</superscript> fish. Further, using a novel object approach (NOA) test, we found that aged (3-year-old) prp2 <superscript>-/-</superscript> fish approached the novel object more than either age-matched prp2 <superscript>+/+</superscript> fish or 1-year-old prp2 <superscript>-/-</superscript> fish, but did not have decreased anxiety when we tested them in a novel tank diving test. Taken together, the results of the NOA and novel tank diving tests suggest an altered cognitive appraisal of the novel object in the 3-year-old prp2 <superscript>-/-</superscript> fish. The learning paradigm established here enables a path forward to study PrP <superscript>C</superscript> interactions of relevance to Alzheimer's disease and prion diseases, and to screen for candidate therapeutics for these diseases. The findings underpin a need to consider the relative contributions of loss- versus gain-of-function of PrP <superscript>C</superscript> during Alzheimer's and prion diseases, and have implications upon the prospects of several promising therapeutic strategies.<br />Competing Interests: Competing interestsThe authors declare no competing or financial interests.<br /> (© 2018. Published by The Company of Biologists Ltd.)
Details
- Language :
- English
- ISSN :
- 2046-6390
- Volume :
- 7
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Biology open
- Publication Type :
- Academic Journal
- Accession number :
- 29358166
- Full Text :
- https://doi.org/10.1242/bio.025734