Distribution of big tau isoforms in the human central and peripheral nervous system

‘Big tau’, a longer isoform of tau is expressed in peripheral nervous system (PNS) and specific regions of the central nervous system (CNS). Big tau distribution across the human nervous system and pathophysiological role remains largely unknown. Here, using mass spectrometry, we demonstrate the big tau protein results from the insertion of exon 4a-long in the human MAPT sequence. We observed a central-to-peripheral gradient of big tau expression, lowest in the cortical brain region, followed by the cerebellum, then spinal cord, with the highest level in the human sciatic nerve (PNS). Interestingly, brain regions overlapping with relatively lower big tau are more susceptible to neurofibrillary tangle (NFT) formation. Furthermore, we found that CSF big tau levels did not change with CSF Aβ abnormalities in AD, unlike the CNS tau isoform, which increased significantly with concomitant Aβ and cognitive abnormalities. Our findings provide new insights into the basic biology of big tau in humans, crucial for understanding its pathophysiological functions.