AbstractBackgroundNeuronal death is the result of the neurodegenerative process in Alzheimer’s disease (AD). Both histopathological hallmark lesions of AD, i.e., amyloid plaques and neurofibrillary tangles, are associated with reduced numbers of neurons in the brain. To model AD‐like neuronal death, mouse models with transgenic overexpression of the amyloid precursor protein (APP) and the tau protein can be used. Recently, the necroptotic cell death pathway was found to be activated in the AD brain. In this context, the activated necrosome was found in granulovacuolar degeneration (GVD) lesions in neurons. Therefore, the question arises whether inhibition of the necroptosis pathway reduces neuron loss.MethodWe analyzed APP23xTAU58 double transgenic mice for the presence of the activated necrosome in GVD lesions in association with amyloid and tau pathology. APP23xTAU58 mice at 2, 6, and 12 months of age were studied (n = 5‐10 animals/group). Neuronal densities in the subiculum and the amygdala were compared with those of wildtype littermates. To clarify whether necroptosis inhibitors can interfere with neuron death in this model, we treated APP23xTAU58 mice from 2‐6 months either with dabrafenib or ponatinib (n = 5 animals/group) and compared neuronal densities with that of vehicle‐treated mice. Neuronal densities as well as the percentage of necroptosis markers exhibiting neurons in the subiculum and amygdala were assessed.ResultSix‐ and 12‐month‐old APP23xTAU58 mice showed significantly decreased neuronal densities in the subiculum and amygdala compared to wildtype mice (p < 0.005), as well as an increased number of neurons exhibiting the necroptosis executor pMLKL in GVD lesions (p < 0.0001). Treatment with the necroptosis inhibitors ponatinib and dabrafenib reduced neuronal loss in the subiculum and the amygdala compared to vehicle treatment (p ≤ 0.0002).ConclusionThese results show that neuron loss in the APP23xTAU58 model is associated with the accumulation of necroptosis‐related proteins. This neuron loss and the expression of necrosome components can be reduced by ponatinib or dabrafenib. Thus, it is tempting to speculate that necroptosis inhibition could be a promising strategy to prolong neuron survival and, by doing so, to slow down cognitive decline in AD patients. Funding: FWO