Passive immune clearance is the largest area of active intervention and excitement in the field, with eight novel monoclonal antibodies targeting tau undergoing testing in clinical trials and many more in preclinical development. However, the appropriate tau epitope to target for clearance remains controversial. As mentioned previously, in addition to the classic intraneuronal hyperphosphorylated NFT aggregates, tau is also secreted extracellularly, often in truncated form (eTau), and studies on cerebrospinal fluid from AD patients have found N-terminal fragments and mid-domain regions, without appreciable full length tau or C-terminal fragments. [98] Recent studies have suggested that eTau may induce neuronal hyperexcitability and mediate the transcellular spreading of tau pathology, supporting its role as the pathologic species [99]. This prion-like initial “seeding” of misfolded eTau followed by cell-to-cell propagation along neuronal networks has significant support [85,100], and eTau presents an attractive target for antibody infusion precisely because it is an extracellular process.
