Poster abstracts
Poster number 4 submitted by Grace Cooper
Tau Lys Methylation: A Comparison of 55 and 84 Year Old Normal Human Brain Samples
Grace L Cooper (Ohio State Biochemistry Program), Kristen E Funke (Molecular and Cellular Biochemistry, The Ohio State University), Stefani N Thomas (reenbaum Cancer Center, University of Maryland Baltimore), Jeff Kuret (Molecular and Cellular Biochemistry, The Ohio State University), Austin J Yang (Greenbaum Cancer Center, University of Maryland Baltimore)
Abstract:
Alzheimer’s Disease (AD) is the most common form of dementia, and there is currently no cure or preventative treatment. AD is defined by the appearance of two hallmark lesions: extracellular plaques composed of the beta-amyloid peptide and intracellular neurofibrillary tangles (NFTs) composed of the microtubule-binding protein tau. However, the accumulation of NFTs better correlates with disease and symtom progression. For these reasons, the biology of normal tau protein, and how it malfunctions in disease, is being investigated for clues to the mechanisms underlying AD pathogenesis. Normal tau protein functions in monomeric form to stabilize microtubules and promote their assembly. In AD, tau aggregates into long fibrils that eventually grow to fill the neuronal cytoplasm. Candidate triggers for this conformational change include post translational modifications (PTMs).
Previous data from our lab show the presence of methylation of tau in authentic human brain samples, and demonstrated the potential role of methylation in tau aggregation. Tau was isolated from normal human brain (n = 4; all cases 55 yr old) and analyzed using mass spectrometry, revealing methylation as a novel tau PTM on Lys residues.. In vitro experiments revealed that show that low-occupancy methylation is a normal human tau PTM that does not affect tau’s normal function, but that does depress tau aggregation propensity.
Additionally, authentic human brain samples of 84 year olds were obtained, and characterized using the same mass spectrometry methods as were used for the 55 year old samples to identify methylation sites. Sequence coverage for the two sets of samples were very similar, and no PTM sites were found in an area that was not covered in both the 55 year olds and the 80 year olds. However, fewer sites of methylation were identified, suggesting that methylation may decrease with age. A decrease in methylation could increase tau’s aggregation propensity, leading to more neurofibrillary lesions. We postulate that methylation may decrease with age, causing tau to become more prone to aggregation, and that maintaining or increasing methylation of tau could be a therapeutic approach for slowing the rate and extent of neurofibrillary lesion formation in AD.
Keywords: Alzheimers Disease, Tau Protein, Methylation