Using mass spec-based phosphoproteomics, scientists at the National Institutes of Health's Laboratory of Neurochemistry have characterized the neurofibrillary tangles characteristic of Alzheimer's disease, confirming that, in addition to tau protein, these structures contain a number of other components, including neurofilament proteins and vimentin.
The research, detailed in a paper published in the current issue of the FASEB Journal, offers new insights into the biology of Alzheimer's and suggests potential new protein biomarkers for the disease, said Harish Pant, chief of the laboratory's section on cytoskeleton regulation and leader of the study.
The presence in the brain of neurofibrillary tangles is a hallmark of Alzheimer's disease. These tangles are composed principally of paired helical filaments of which the AD biomarker phosphorylated tau has been identified as a primary component.
Immunohistochemical studies have suggested that phosphorylated neurofilament proteins are also a key component of these PHFs. However, Pant told ProteoMonitor, due to questions of cross-reactivity antibodies to phosphorylated neurofilament proteins with phospho-tau, these studies have been considered inconclusive.
"No one said that they weren't there," he said, "but there was no conclusive evidence. These antibodies are not that specific and react with other similar epitopes, so [researchers] said that what they were recognizing was phosphorylated tau proteins" and not the neurofilament proteins.
Via mass spec analysis of neurofibrillary tangles on a Thermo Scientific LTQ XL instrument, Pant's team demonstrated that, in fact, phosphorylated neurofilament proteins are one of the tangles' components, identifying phosphopeptides from the NF-M and NF-H forms of the protein as well as non-phosphorylated peptides from the NF-L form of the protein along with the intermediate filament protein vimentin.
Their investigation also identified phosphopeptides from the MAP1 and MAP2 proteins, as well as non-modified peptides from MAP1B, MAP2, MAP4, and MAP6.
Pant said he now hopes to investigate whether these phosphorylated neurofilament proteins might prove useful as protein biomarkers for Alzheimer's. Along with the protein Abeta1-42, tau and phospho-tau are among the best studied markers for the disease. According to the FASEB Journal paper, the phosphorylated neurofilaments could serve a similar role, with the authors suggesting that "neuronal death and degeneration may release fragments of these proteins into body fluids at sufficient levels to be easily detected by specific antibodies at early, preclinical stages of AD."
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