Alzheimer’s disease‐related necroptotic pathology: An exclusive presence of the necrosome in granulovacuolar degeneration inclusions in human and transgenic mouse brains

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is characterized by pathological processes such as β‐amyloid (Aβ) plaques, neurofibrillary tangles (NFT), cytoplasmic granulovacuolar degeneration (GVD) lesions and neuronal loss that underpin cognitiveand behavioral alterations. Necroptosis, a programmed form of cell death defined by the assembly of the necrosome complex composed of phosphorylated proteins (pRIPK1, pRIPK3 and pMLKL), has recently been shown to be involved in AD.MethodTo determine the neuropathological characteristics and distribution pattern of the necrosome components, we performed a comprehensive immunohistochemical analysis of brains of AD, pathologically defined preclinical AD and non‐AD control cases. A similar analysis was carried out to investigate necroptosis‐related proteins in transgenic mouse models of Aβ and Tau pathology.ResultsWe identified all three activated necrosome components (pRIPK1, pRIPK3 and pMLKL) in GVD inclusionswithin neurons of the hippocampal subfields CA1, CA2/3, CA4, dentate gyrus, subiculum, entorhinal cortex, temporal cortex, hypothalamus, amygdala and frontal cortex of symptomatic and preclinical AD patients. The three necrosome proteins colocalized with standard GVD markers, such as pTDP‐43 and CK1δ, and similarly to these markers detected GVD lesions. Necrosome‐associated GVD neurons inversely correlated with neuronal density in the early affected hippocampus and in the late affected frontal cortex. Necroptosis‐specific GVD lesions showed strong positive associations with AD‐defining parameters, showing the strongest correlation and partial colocalization with Tau pathology. Moreover, we analyzed brain tissues of transgenic mice carrying mutated APP, Tau or both transgenes. We found morphologically comparable GVD lesions positive for the necroptosis components in the subiculum, hippocampus and entorhinal cortex of 12‐month‐old APP23xTAU58 mice. We confirmed mouse necrosome‐positive GVD inclusions by CK1δ immunoreactivity.ConclusionThe presence of the necrosome in GVD inclusions points to a specific form of necroptosis in AD that can be modelled in APPxTAU transgenic mice, possibly indicating Tau and/or Aβ as drivers of this pathology. Necrosome‐positive GVD granules represent a potential protective system sequestering the necrosome complex, which could interfere with or delay necroptosis‐related neuronal death.