An ancient conserved role for prion protein in learning and memory.

The misfolding of cellular prion protein (PrPC ) to form PrP Scrapie (PrPSc ) is an exemplar of toxic gain-of-function mechanisms inducing propagated protein misfolding and progressive devastating neurodegeneration. Despite this, PrPC function in the brain is also reduced and subverted during prion disease progression; thus understanding the normal function of PrPC in healthy brains is key. Disrupting PrPC 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, PrPC 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 PrPC 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 PrPC 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 PrPC 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 PrPC during Alzheimer's and prion diseases, and have implications upon the prospects of several promising therapeutic strategies.