Is Tau Acetylation a Key to Frontotemporal Lobar Degeneration Diagnosis?

Tau protein misfolding and deposition in the brain is a common factor across many neurodegenerative diseases, grouped under the term tauopathies. These can be divided into primary tauopathies, where tau is the sole aggregating protein, and secondary tauopathies, in which tau aggregates in response to other disease processes, e.g., amyloid β aggregation. In physiological conditions, tau acts as a stabilizing agent for microtubules; the poly-tubulin cylindrical structures that serve as both part of the cytoskeleton and internal transport tracks inside axons. However, in some conditions, tau detaches from the microtubules and may bind to other strands of tau protein and its fragments, forming oligomers and larger aggregates. This can be the result of a mutation in the microtubule-associated protein tau (MAPT) gene, hyperphosphorylation, or other, not yet known, reasons. Tau fragments are known to be released from neurons and move from the brain interstitial fluid into cerebrospinal fluid (CSF) and across the blood–brain barrier into plasma, where they can be measured as biomarkers. Total-tau (t-tau) and brain-derived-tau are indicators of axonal degeneration, and their high levels in biofluids, in the absence of phosphorylated tau (p-tau) biomarkers, suggest acute neuronal injury, as, for example, in stroke, brain trauma, or Creutzfeldt–Jakob disease. P-tau peptides, such as p-tau181, p-tau217, and p-tau231, are characteristic of Alzheimer disease (AD) pathology. The availability of blood-based biomarkers has changed the field of AD research immensely, enabling ante-mortem diagnosis and classification of patients for involvement into clinical trials of disease-modifying treatments. This, however, is not the case with primary tauopathies, which still lack validated biomarkers.