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Acta Neuropathol. 2019 Dec 4. doi: 10.1007/s00401-019-02103-y. [Epub ahead of print]

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

Author information

1
Laboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), O&N IV, Herestraat 49, box 1032, 3000, Leuven, Belgium.
2
Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), O&N IV Herestraat 49, box 602, 3000, Leuven, Belgium.
3
Center for Brain and Disease Research, VIB, Leuven, Belgium.
4
Laboratory for Neurobiology, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium.
5
Department of Neurosciences, Experimental Neurology Group, KU Leuven, Leuven, Belgium.
6
Department of Neurology, UZ Leuven, Leuven, Belgium.
7
Department of Geriatric Psychiatry, University Hospitals Leuven, Leuven, Belgium.
8
Department of Neurology, University of Ulm, Ulm, Germany.
9
Department of Geriatrics, University Medical Center Göttingen, Göttingen, Germany.
10
Department of Pathology, University Hospital Leuven, Leuven, Belgium.
11
Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), O&N IV Herestraat 49, box 602, 3000, Leuven, Belgium. bart.destrooper@kuleuven.vib.be.
12
Center for Brain and Disease Research, VIB, Leuven, Belgium. bart.destrooper@kuleuven.vib.be.
13
Department of Pathology, University Hospital Leuven, Leuven, Belgium. bart.destrooper@kuleuven.vib.be.
14
Laboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), O&N IV, Herestraat 49, box 1032, 3000, Leuven, Belgium. dietmar.thal@kuleuven.be.
15
Department of Pathology, University Hospital Leuven, Leuven, Belgium. dietmar.thal@kuleuven.be.

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.

KEYWORDS:

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

PMID:
31802237
DOI:
10.1007/s00401-019-02103-y

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