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

Objective: To characterize the distribution of "big tau," a longer tau isoform expressed in the peripheral nervous system (PNS) and select central nervous system (CNS) regions, and to examine its relationship with aging and neurodegeneration. Methods: We performed mass spectrometric sequencing of big tau sequence and mapped its distribution across the human nervous system. Postmortem samples included brains from Alzheimer's disease (AD), disease controls, and amyotrophic lateral sclerosis (ALS); spinal cord from young controls, disease controls and ALS; and peripheral nerves. Big and small tau levels were also quantified in the cerebrospinal fluid (CSF) from young normal controls, amyloid positive and amyloid negative participants. Results: Human 'big tau' results from the insertion of 355 amino acids in the tau protein, encoded by the exon 4a-long and not exon 4a-short. Alternative splicing of exons 2, 3, and 10 generates multiple big tau isoforms, expanding the known human tau repertoire. Total tau concentration is ~ 1000-fold higher in the brain than in PNS, where big tau rises sharply along a central-to-peripheral gradient, comprising ~ 50 % of total tau in peripheral nerves compared to only ~ 1 % in brain. CSF big tau levels remain unaltered with CSF Aβ abnormalities in AD, unlike the small tau isoform, which increases significantly with concomitant Aβ and cognitive abnormalities. Interpretation: Big tau exhibits a distinct distribution in the human nervous system, decoupled from the changes associated with brain-derived small tau in AD. These findings open opportunities for developing specific blood-based biomarkers to differentiate CNS versus PNS disorders.