Distribution of big tau isoforms in the human central and peripheral nervous system
ObjectiveTau is widely studied in the field of neurodegenerative disease research, yet most work has focused on canonical brain tau isoforms. A longer isoform, "big tau," produced by inclusion of exon 4a, is expressed in the peripheral nervous system (PNS) and select central nervous system (CNS) regions. We sought to characterize big tau molecular composition, anatomical distribution, and relevance to neurodegenerative disease. MethodsMass spectrometry was used to sequence big tau and map its distribution across the human nervous system. Postmortem samples included brain tissue from Alzheimers disease (AD), amyotrophic lateral sclerosis (ALS), and controls; spinal cord from ALS and controls; and peripheral nerves. Big and canonical ("small") tau isoforms were also quantified in cerebrospinal fluid (CSF) from young controls and participants stratified by amyloid status and cognitive impairment. ResultsHuman big tau results from insertion of either 355 or 251 amino acids encoded by exon 4a-long and exon 4a-short, respectively. Alternative splicing of exons 2, 3, and 10 generates multiple big tau isoforms. Total tau levels were [~]1000-fold higher in brain than in the PNS; however, the relative abundance of big tau increased from the CNS to the PNS, comprising 50 % of the total tau in the periphery and exhibiting considerable regional heterogeneity in the brain ([~] 1 % of total tau). In CSF, big tau levels were unchanged by amyloid abnormalities or cognitive impairment, whereas canonical tau increased with AD-related pathology. InterpretationBig tau represents a distinct tau population enriched in the PNS and largely uncoupled from disease-associated changes in brain-derived tau, suggesting that distinguishing big tau from canonical tau may improve interpretation of tau biomarkers and help differentiate CNS neurodegeneration from peripheral nerve pathology.