Aβ-induced acceleration of Alzheimer-related τ-pathology spreading and its association with prion protein
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.
KeywordsTau-protein Amyloid-β Cross seeding Alzheimer’s disease Transgenic mice Neuropathology Prion protein
We thank Dr. Peter Davies, Department of Pathology, Albert Einstein College of Medicine, USA for the gift of the PHF1 and TG3 antibodies and Dr. Marcus Fändrich, Institute of Pharmaceutical Biotechnology, Center for Biomedical Research, University of Ulm, Germany for the gift of B10AP antibody fragments. The administrative and technical help of Mrs. Alicja Ronisz is gratefully acknowledged.
Study design: DRT and MS; biochemistry: SAH, LAG, ARU, PLB, VU, KB, RF, CG, and MW; histology: SAH, ARU, MJK, SO, LAG, and DRT; animal experiments: JR, SR, and MS; neuropathology: DRT and TT; clinical neurology: RV and CAFA. Statistical analysis: DRT, LAG, and SAH. Data interpretation: DRT, LAG, and SAH; manuscript preparation: SAH, LAG, and DRT; critical manuscript review: ARU, KB, MJK, SO, PLB, VU, JR, SR, RV, CAFA, TT, RF, CG, MW, and MS.
Alzheimer Forschung Initiative (AFI) #10810 (DRT); Fonds Wetenschappelijk Onderzoek (FWO) G0F8516N (DRT, RV); Vlaamse Impulsfinanciering voor Netwerken voor Dementie-onderzoek (IWT 135043) (RV, DRT).
Compliance with ethical standards
Conflict of interest
DRT received consultant honorary from GE-Healthcare (UK), and Covance Laboratories (UK), speaker honorary from Novartis Pharma AG (Switzerland), travel reimbursement from GE-Healthcare (UK), and UCB (Belgium), and collaborated with Novartis Pharma AG (Switzerland), Probiodrug (Germany), GE-Healthcare (UK), and Janssen Pharmaceutical Companies (Belgium). JR and MS were employees of Novartis Pharma Basel and SR is employee of Novartis Pharma Basel (Switzerland). CAFvA received honoraria from serving on the scientific advisory board of Nutricia GmbH (2014), Roche (2018) and Honkong University Research Council (2014) and has received funding for travel and speaker honoraria from Nutricia GmbH (2014–2015), Lilly Deutschland GmbH (2013–2016), Desitin Arzneimittel GmbH (2014), Biogen (2016–2018), Roche (2017–2018), and Dr. Willmar Schwabe GmbH&Co. KG (2014–2015).
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