Necrosome complex detected in granulovacuolar degeneration is associated with neuronal loss in Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is characterized by a specific pattern of neuropathological changes, including extracellular amyloid β (Aβ) deposits, intracellular neurofibrillary tangles (NFTs), granulovacuolar degeneration (GVD) representing cytoplasmic vacuolar lesions, synapse dysfunction and neuronal loss. Necroptosis, a programmed form of necrosis characterized by the assembly of the necrosome complex composed of phosphorylated proteins, i.e. receptor-interacting serine/threonine-protein kinase 1 and 3 (pRIPK1 and pRIPK3) and mixed lineage kinase domain-like protein (pMLKL), has recently been shown to be involved in AD. However, it is not yet clear whether necrosome assembly takes place in brain regions showing AD-related neuronal loss and whether it is associated with AD-related neuropathological changes. Here, we analyzed brains of AD, pathologically defined preclinical AD (p-preAD) and non-AD control cases to determine the neuropathological characteristics and distribution pattern of the necrosome components. We demonstrated that all three activated necrosome components can be detected in GVD lesions (GVDn+, i.e. GVD with activated necrosome) in neurons, that they colocalize with classical GVD markers, such as pTDP-43 and CK1δ, and similarly to these markers detect GVD lesions. GVDn + neurons inversely correlated with neuronal density in the early affected CA1 region of the hippocampus and in the late affected frontal cortex layer III. Additionally, AD-related GVD lesions were associated with AD-defining parameters, showing the strongest correlation and partial colocalization with NFT pathology. Therefore, we conclude that the presence of the necrosome in GVD plays a role in AD, possibly by representing an AD-specific form of necroptosis-related neuron death. Hence, necroptosis-related neuron loss could be an interesting therapeutic target for treating AD.

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Acknowledgements

The authors gratefully acknowledge the assistance of Mrs. Alicja Ronisz. They also thank Mathias De Decker (Laboratory for Neurobiology, VIB-KU Leuven, Belgium) for providing SH-SY5Y cells. Also, we thank the VIB Imaging Core Facility in Leuven for expert assistance and overall technical support in super-resolution imaging of cleared tissue using spinning disk confocal microscopy. The study was supported by: Fonds Wetenschappelijk Onderzoek (FWO) G0F8516N, 1S46219N, (DRT, RV); C1-internal funds from KU Leuven C14-17-107 (DRT); Vlaamse Impulsfinanciering voor Netwerken voor Dementie-onderzoek (IWT 135043) (RV, BDS, DRT) and a Methusalem grant of the Flemish Government and the KU Leuven to BDS. EVS is funded by an SB PhD Fellowship of FWO-Vlaanderen (1S46219N). SB received a post-doc fellowship from FWO-Vlaaderen (12P5919N).

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Correspondence to Bart De Strooper or Dietmar Rudolf Thal.

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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). BDS collaborated with Janssen Pharmaceutical companies (Belgium), Abbvie (USA) and received consulting fees from Eisai (Japan). None related to the work in this paper. RV’s institution has clinical trial agreements (RV as PI) with AbbVie, Genentech, Novartis, and Roche, material transfer agreements (RV as PI) with Avid a subsidiary of EliLilly, and consultancy agreements (RV as PI) with Prevail Therapeutics and Rodin Therapeutics. CAFvA received honoraria from serving on the scientific advisory board of Nutricia GmbH, Roche, Dr. Willmar Schwabe GmbH and Honkong University Research council and has received funding for travel and speaker honoraria from Nutricia GmbH, Lilly Deutschland GmbH, Desitin Arzneimittel GmbH, Biogen, Roche and Dr. Willmar Schwabe GmbH &Co. KG.

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Koper, M.J., Van Schoor, E., Ospitalieri, S. et al. Necrosome complex detected in granulovacuolar degeneration is associated with neuronal loss in Alzheimer’s disease. Acta Neuropathol 139, 463–484 (2020). https://doi.org/10.1007/s00401-019-02103-y

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Keywords

  • Necroptosis
  • Granulovacuolar degeneration
  • Alzheimer’s disease
  • Neuronal loss
  • Necrosome
  • pMLKL