Progression of Seed-Induced Aß Deposition within the Limbic Connectome.

ABSTRACT

An important early event in the pathogenesis of Alzheimer's disease (AD) is the aberrant polymerization and extracellular accumulation of amyloid-ß peptide (Aß). In young transgenic mice expressing the human Aß-precursor protein (APP), deposits of Aß can be induced by the inoculation of minute amounts of brain extract containing Aß aggregates ("Aß seeds"), indicative of a prion-like seeding phenomenon. Moreover, focal intracerebral injection of Aß seeds can induce deposits not only in the immediate vicinity of the injection site, but, with time, also in distal regions of the brain. However, it remains uncertain whether the spatial progression of Aß deposits occurs via nonsystematic diffusion from the injection site to proximal regions or via directed transit along neuroanatomical pathways. To address this question, we analyzed the spatiotemporal emergence of Aß deposits in two different APP-transgenic mouse models that had been previously inoculated with Aß seeds into the hippocampal formation. The results revealed a specific, neuroanatomically constrained pattern of induced Aß deposits in structures corresponding to the limbic connectome, supporting the hypothesis that neuronal pathways act as conduits for the movement of proteopathic agents among brain regions, thereby facilitating the progression of disease.