Koper, MJ;
Van Schoor, E;
Ospitalieri, S;
Vandenberghe, R;
Vandenbulcke, M;
von Arnim, CAF;
Tousseyn, T;
... Thal, DR; + view all
(2020)
Necrosome complex detected in granulovacuolar degeneration is associated with neuronal loss in Alzheimer's disease.
Acta Neuropathologica
, 139
pp. 463-484.
10.1007/s00401-019-02103-y.
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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.
| Type: | Article |
|---|---|
| Title: | Necrosome complex detected in granulovacuolar degeneration is associated with neuronal loss in Alzheimer's disease |
| Location: | Germany |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1007/s00401-019-02103-y |
| Publisher version: | https://doi.org/10.1007/s00401-019-02103-y |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Alzheimer’s disease, Granulovacuolar degeneration, Necroptosis, Necrosome, Neuronal loss, pMLKL |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UK Dementia Research Institute HQ |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10088034 |
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