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

• Published in: Acta neuropathologica Vol. 139; no. 3; pp. 463 - 484
• Main Authors: Koper, Marta J., Van Schoor, Evelien, Ospitalieri, Simona, Vandenberghe, Rik, Vandenbulcke, Mathieu, von Arnim, Christine A. F., Tousseyn, Thomas, Balusu, Sriram, De Strooper, Bart, Thal, Dietmar Rudolf
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-03-2020; Springer; Springer Nature B.V
• Subjects: Adolescent; Adult; Advertising executives; Aged; Aged, 80 and over; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid; Brain; Brain - metabolism; Brain - pathology; Cell death; Cortex (frontal); Female; Humans; Kinases; Lesions; Male; MAP kinase; Medicine; Medicine & Public Health; Middle Aged; Necroptosis; Necroptosis - physiology; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Neurodegeneration; Neurodegenerative diseases; Neurofibrillary tangles; Neurons; Neurons - pathology; Neuropathology; Neurophysiology; Neurosciences; Original Paper; Pathology; Physiological aspects; Protein kinase; Protein kinases; Therapeutic applications; Threonine; Young Adult; Granulovacuolar degeneration; Necrosome; Neuronal loss; Alzheimer’s disease; Necroptosis; pMLKL
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-019-02103-y

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.