It may take inflammation, phosphorylation and ubiquitination to 'tangle' in Alzheimer's disease.

Neurofibrillary tangles (NFT) are one of the pathologic hallmarks of Alzheimer's disease (AD). Their major component is tau, a protein that becomes hyperphosphorylated and accumulates into insoluble paired helical filaments. During the course of the disease such filaments aggregate into bulky NFT that get ubiquitinated. What triggers their formation is not known, but neuroinflammation could play a role. Neuroinflammation is an active process detectable in the earliest stages of AD. The neuronal toxicity associated with inflammation makes it a potential risk factor in the pathogenesis of chronic neurodegenerative diseases, such as AD. Determining the sequence of events that lead to this devastating disease has become one of the most important goals for AD prevention and treatment. In this review we focus on three topics relevant to AD pathology and to NFT formation: (1) what triggers CNS inflammation resulting in glia activation and neuronal toxicity; (2) how products of inflammation might change the substrate specificity of kinases/phosphatases leading to tau phosphorylation at pathological sites; (3) the relationship between the ubiquitin/proteasome pathway and tau ubiquitination and accumulation in NFT. The overall aim of this review is to provide a challenging and sometimes provocative survey of important contributions supporting the view that CNS inflammation might be a critical contributor to AD pathology. Neuronal cell death resulting from neuroinflammatory processes may have devastating effects as, in the vast majority of cases, neurons lost to disease cannot be replaced. In order to design therapies that will prevent endangered neurons from dying, it is critical that we learn more about the effects of neuroinflammation and its products.