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Acta Neuropathol. 2019 Dec;138(6):913-941. doi: 10.1007/s00401-019-02053-5. Epub 2019 Aug 14.

Aβ-induced acceleration of Alzheimer-related τ-pathology spreading and its association with prion protein.

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Laboratory for Neuropathology, Department of Imaging and Pathology, KU-Leuven, Leuven, Belgium.
Leuven Brain Institute, KU-Leuven, Leuven, Belgium.
Laboratory for Neuropathology, Institute of Pathology, University of Ulm, Ulm, Germany.
Anasthesiology and Intensive Medicine, University Hospital of Tübingen, Tübingen, Germany.
Department of Gene Therapy, University of Ulm, Ulm, Germany.
Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, KU Leuven (University of Leuven), Leuven, Belgium.
VIB, Center for Brain and Disease Research, Leuven, Belgium.
Department of Neurosciences, KU-Leuven, Leuven, Belgium.
Novartis Institutes for Biomedical Sciences, Basel, Switzerland.
Experimental Neurology Group, Department of Neurosciences, KU Leuven, Leuven, Belgium.
Department of Neurology, UZ-Leuven, Leuven, Belgium.
Department of Neurology, University of Ulm, Ulm, Germany.
Clinic for Neurogeriatrics and Neurological Rehabilitation, University- und Rehabilitation Hospital Ulm (RKU), Ulm, Germany.
Department of Pathology, UZ Leuven, Leuven, Belgium.
Institute for Diabetes and Obesity, Monoclonal Antibody Research Group, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Munich, Germany.
German Center for Neurodegenerative Diseases (DZNE) Munich, 81377, Munich, Germany.
Munich Cluster for Systems Neurology (SyNergy), 81377, Munich, Germany.
Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-University Munich, 81377, Munich, Germany.
Laboratory for Neuropathology, Department of Imaging and Pathology, KU-Leuven, Leuven, Belgium.
Leuven Brain Institute, KU-Leuven, Leuven, Belgium.
Laboratory for Neuropathology, Institute of Pathology, University of Ulm, Ulm, Germany.
Department of Pathology, UZ Leuven, Leuven, Belgium.


Extracellular deposition of amyloid β-protein (Aβ) in amyloid plaques and intracellular accumulation of abnormally phosphorylated τ-protein (p-τ) in neurofibrillary tangles (NFTs) represent pathological hallmark lesions of Alzheimer's disease (AD). Both lesions develop in parallel in the human brain throughout the preclinical and clinical course of AD. Nevertheless, it is not yet clear whether there is a direct link between Aβ and τ pathology or whether other proteins are involved in this process. To address this question, we crossed amyloid precursor protein (APP) transgenic mice overexpressing human APP with the Swedish mutation (670/671 KM → NL) (APP23), human wild-type APP (APP51/16), or a proenkephalin signal peptide linked to human Aβ42 (APP48) with τ-transgenic mice overexpressing human mutant 4-repeat τ-protein with the P301S mutation (TAU58). In 6-month-old APP23xTAU58 and APP51/16xTAU58 mice, soluble Aβ was associated with the aggravation of p-τ pathology propagation into the CA1/subiculum region, whereas 6-month-old TAU58 and APP48xTAU58 mice neither exhibited significant amounts of p-τ pathology in the CA1/subiculum region nor displayed significant levels of soluble Aβ in the forebrain. In APP23xTAU58 and APP51/16xTAU58 mice showing an acceleration of p-τ propagation, Aβ and p-τ were co-immunoprecipitated with cellular prion protein (PrPC). A similar interaction between PrPC, p-τ and Aβ was observed in human AD brains. This association was particularly noticed in 60% of the symptomatic AD cases in our sample, suggesting that PrPC may play a role in the progression of AD pathology. An in vitro pull-down assay confirmed that PrPC is capable of interacting with Aβ and p-τ. Using a proximity ligation assay, we could demonstrate proximity (less than ~ 30-40 nm distance) between PrPC and Aβ and between PrPC and p-τ in APP23xTAU58 mouse brain as well as in human AD brain. Proximity between PrPC and p-τ was also seen in APP51/16xTAU58, APP48xTAU58, and TAU58 mice. Based on these findings, it is tempting to speculate that PrPC is a critical player in the interplay between Aβ and p-τ propagation at least in a large group of AD cases. Preexisting p-τ pathology interacting with PrPC, thereby, appears to be a prerequisite for Aβ to function as a p-τ pathology accelerator via PrPC.


Alzheimer’s disease; Amyloid-β; Cross seeding; Neuropathology; Prion protein; Tau-protein; Transgenic mice


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