Abeta prion spreading: correlation with behavior, prion protein cofactor and effect of somatic mutations in novel animal models

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Alzheimer s disease (AD) is the most prevalent neurodegenerative disease with currently no curative therapy available. According to the amyloid cascade hypothesis of AD pathogenesis, aberrant APP processing leading to increased Abeta 42 levels and its multimerization are an essential trigger. In recent years, evidence has accumulated indicating that as an additional, accelerating disease mechanism in experimental AD models, aggregated Abeta can spread throughout the brain by inducing conversion of other Abeta molecules that are not yet in a pathogenic, aggregated state, thereby replicating its pathological conformer/multimer by a prion-like mechanism. Such a mechanism would also support the somatic mutation hypothesis that states that Abeta aggregation could be started by few neurons expressing mutant APP genes. The shortcoming of animal models used so far for these experiments is that they are prone to spontaneous, endogenous AD-like pathology that by inoculations is only accelerated and not generated de novo. In this project, advantage will be taken of a novel animal model for early AD, a transgenic mouse that expresses exclusively dimeric Abeta crosslinked through a disulfide bridge (tgDimer mouse, Müller-Schiffmann et al., 2016, Brain 139:509-25) that does not develop insoluble Abeta plaques or neuropathology spontaneously, but can be induced to associate to existing plaques. Here, by using our unique animal model, we will answer three questions that are of outstanding importance and have not been answered so far: 1. How does Abeta prion spreading relate to behavioral changes? 2. What role has PrP as a cofactor for the behavioral changes during Abeta spreading or Abeta spreading itself? 3. To what extent can somatic mutations of AD-causing genes in neurons trigger AD? We will use the tgDimer mouse, and a new line where the tgDimer mouse is crossed into the PrP ko background, and breed those two lines into the GFAP-luciferase mouse where Abeta plaque spreading can be monitored through in vivo biolouminescence detection. Systematic inoculations with two AD strains and two synthetic Abeta strains will be perfromed and a battery of behavioral tests, both classical (e.g. Morris water maze) and using automated behavioral analysis. For testing in how far somatic mutations can trigger abeta prion spreading, we will perform in utero electroporation of mutant human APP / presenilin 1 into the tgDimer and APP 23 /GFAP-luciferase mouse which leads to expression of human mutant APP in a limited amount of neurons, potentially triggering Abeta spreading. At the end of this project, we will have detailed knowledge on how Abeta spreading related to which behavioral changes, a definite answer on the role of PrP in Abeta prion spreading and modulation of behavioral response, as well as delineate the role of somatic mutations in the pathogenesis of AD. These results may open new avenues in much-needed therapeutic research in AD.