A beta-induced acceleration of Alzheimer-related tau-pathology spreading and its association with prion protein
| Autor: | Thomas Tousseyn, Julia Reichwald, Pablo Largo-Barrientos, Michael Willem, Rik Vandenberghe, Valerie Uytterhoeven, Luis Aragão Gomes, Karthikeyan Balakrishnan, Simona Ospitalieri, Matthias Staufenbiel, Marta J. Koper, Dietmar Rudolf Thal, Christine A. F. von Arnim, Silvia Andrea Hipp, Ajeet Rijal Upadhaya, Sabine Rabe, Regina Feederle, Camilla Giudici |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Pathology Plaque Amyloid Proximity ligation assay Tau-protein Amyloid beta-Protein Precursor pathology [Alzheimer Disease] 0302 clinical medicine pathology [Brain] metabolism [Amyloid beta-Protein Precursor] Amyloid precursor protein Transgenic mice Senile plaques Neuropathology biology Chemistry Brain Neurofibrillary Tangles Human brain medicine.anatomical_structure Alzheimer’s disease metabolism [Alzheimer Disease] Genetically modified mouse medicine.medical_specialty Amyloid Amyloid beta Tau protein metabolism [Amyloid beta-Peptides] tau Proteins Mice Transgenic genetics [Mutation] Prion Proteins Pathology and Forensic Medicine 03 medical and health sciences Cellular and Molecular Neuroscience metabolism [Prion Proteins] Alzheimer Disease mental disorders medicine Animals Humans Amyloid-β ddc:610 pathology [Plaque Amyloid] Cross seeding Amyloid beta-Peptides metabolism [tau Proteins] Disease Models Animal 030104 developmental biology Prion protein metabolism [Brain] Mutation biology.protein Neurology (clinical) pathology [Neurofibrillary Tangles] 030217 neurology & neurosurgery |
| Zdroj: | Acta neuropathologica 138(6), 913-941 (2019). doi:10.1007/s00401-019-02053-5 |
| DOI: | 10.1007/s00401-019-02053-5 |
| Popis: | 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. ispartof: ACTA NEUROPATHOLOGICA vol:138 issue:6 pages:913-941 ispartof: location:Germany status: published |
| Databáze: | OpenAIRE |
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