Abstract

AbstractBackgroundSpreading of tau pathology between connected brain regions correlates with disease progression in Alzheimer’s disease (AD) and gives rise to distinct neuropathological stages. While seeding and spreading of tau pathology has been reproduced in cell and animal models, the understanding of the molecular pathways mediating tau spread remains limited. Binding of tau fibrils to the extracellular region of the Amyloid Precursor Protein (APP) was reported to result in the uptake of tau in a cell culture model. This raised the question whether APP may function as a tau fibril receptor during the trans‐neuronal spread of tau pathology in vivo, thereby contributing to disease progression.MethodTo study the effect of APP expression on tau spread we (1) injected APP KO mice with human AD brain extracts and analysed induction of tau pathology; (2) expressed an AAV‐based reporter construct in APP KO and KI mice and analyse tau spread; (3) cultured APP KO primary neurons in microfluidic devices and analysed tau spread (4) stimulated brain slices and primary neurons from APP KO and KI mice and analysed tau release.Result(1) AD brain extracts failed to induce tau pathology in APP KO mice; (2) APP KO mice showed reduced spreading of AAV‐dependent expression of human tau, whereas mutant human APP mice showed increased spread of tau; (3) spread of tau between connected neurons was reduced in microfluidic devices containing APP KO neurons compared to wild type neurons; (4) brain slices and primary neurons from APP KO mice showed reduced tau release after neuronal stimulation, whereas tissue from mutant human APP mice showed increase release of tau.ConclusionAPP facilitates neuronal release and spreading of tau. This process is augmented by pathogenic APP mutations and increased APP levels, and reduced in the absence of APP. Our data suggest APP as an integral part of spreading of tau pathology and delineates a novel role for pathogenic APP mutations in AD.

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