TNF-mediated neuroinflammation is linked to neuronal necroptosis in Alzheimer's disease hippocampus.

The pathogenetic mechanisms underlying neuronal death and dysfunction in Alzheimer's disease (AD) remain unclear. However, chronic neuroinflammation has been implicated in stimulating or exacerbating neuronal damage. The tumor necrosis factor (TNF) superfamily of cytokines are involved in many systemic chronic inflammatory and degenerative conditions and are amongst the key mediators of neuroinflammation. TNF binds to the TNFR1 and TNFR2 receptors to activate diverse cellular responses that can be either neuroprotective or neurodegenerative. In particular, TNF can induce programmed necrosis or necroptosis in an inflammatory environment. Although activation of necroptosis has recently been demonstrated in the AD brain, its significance in AD neuron loss and the role of TNF signaling is unclear. We demonstrate an increase in expression of multiple proteins in the TNF/TNF receptor-1-mediated necroptosis pathway in the AD post-mortem brain, as indicated by the phosphorylation of RIPK3 and MLKL, predominantly observed in the CA1 pyramidal neurons. The density of phosphoRIPK3 + and phosphoMLKL + neurons correlated inversely with total neuron density and showed significant sexual dimorphism within the AD cohort. In addition, apoptotic signaling was not significantly activated in the AD brain compared to the control brain. Exposure of human iPSC-derived glutamatergic neurons to TNF increased necroptotic cell death when apoptosis was inhibited, which was significantly reversed by small molecule inhibitors of RIPK1, RIPK3, and MLKL. In the post-mortem AD brain and in human iPSC neurons, in response to TNF, we show evidence of altered expression of proteins of the ESCRT III complex, which has been recently suggested as an antagonist of necroptosis and a possible mechanism by which cells can survive after necroptosis has been triggered. Taken together, our results suggest that neuronal loss in AD is due to TNF-mediated necroptosis rather than apoptosis, which is amenable to therapeutic intervention at several points in the signaling pathway.

Peripheral Biomarkers for Early Detection of Alzheimer's and Parkinson's Diseases.

Neurological disorders are found to be influencing the peripheral tissues outside CNS. Recent developments in biomarkers for CNS have emerged with various diagnostic and therapeutic shortcomings. The role of central biomarkers including CSF-based and molecular imaging-based probes are still unclear for early diagnosis of major neurological diseases. Current trends show that early detection of neurodegenerative diseases with non-invasive methods is a major focus of researchers, and the development of biomarkers aiming peripheral tissues is in demand. Alzheimer's and Parkinson's diseases are known for the progressive loss in neural structures or functions, including the neural death. Various dysfunctions of metabolic and biochemical pathways are associated with early occurrence of neuro-disorders in peripheral tissues including skin, blood cells, and eyes. This article reviews the peripheral biomarkers explored for early detection of Alzheimer's and Parkinson's diseases including blood cells, skin fibroblast, proteomics, saliva, olfactory, stomach and colon, heart and peripheral nervous system, and others. Graphical Abstract.