An ancient conserved role for prion protein in learning and memory

The misfolding of cellular prion protein (PrP^C) to form PrP Scrapie (PrP^Sc) is an exemplar of toxic gain-of-function mechanisms inducing propagated protein misfolding and progressive devastating neurodegeneration. Despite this, PrP^C function in the brain is also reduced and subverted during prion disease progression; thus understanding the normal function of PrP^C in healthy brains is key. Disrupting PrP^C 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^C 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^C in memory using a disparate animal model, the zebrafish. Here we document an age-dependent memory decline in prp2^-/- zebrafish, pointing to a conserved and ancient role of PrP^C in memory. Specifically, we found that aged (3-year-old) prp2^-/- fish performed poorly in an object recognition task relative to age-matched prp2^+/+ fish or 1-year-old prp2^-/- fish. Further, using a novel object approach (NOA) test, we found that aged (3-year-old) prp2^-/- fish approached the novel object more than either age-matched prp2^+/+ fish or 1-year-old prp2^-/- 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^-/- fish. The learning paradigm established here enables a path forward to study PrP^C 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^C during Alzheimer's and prion diseases, and have implications upon the prospects of several promising therapeutic strategies.