**3.5. Tau truncated forms**

A growing body of literature is pointing to tau fragments, produced by cleavage events, as major players in the onset and the progression of the pathology [126–129]. In AD brains, after an initial misfolding at early stages of the disease which involves the physical contact of the N-terminal region with the microtubule binding repeats, tau is cleaved first at residue D421 followed by cleavage at residue E391, while N-terminal cleavage appears in later stages of the disease [126, 130]. The differential enzymatic cleavages during the pathological process is mostly dependent on Caspases activation, which lead to the generation of several tau fragments, each displaying its own profile of neurotoxicity [131]. Additionally, Calpain proteases have been shown to produce a triplet of tau fragments spanning from 35 kDa to 15 kDa. Similarly to full length tau [132, 133], several reports have shown that tau fragments can be secreted and uptaken from cells and brain slices and mediate toxicity [134–136].

These and other findings led researchers to investigate the presence of tau fragments in CSF and other biological fluids as potential biomarkers for the differential diagnosis of tauopathies and associated diseases. In CSF, at least 10 fragments were characterized in AD by mass spectrometry [137]. The presence of the 20 kDa caspase-6 cleavage product of tau in the CSF of AD has been reported to be associated with brain pathology and was found to be increased with the severity of the disease and the overall measure of global cognition [138]. Other reports found a 26–28 kDa fragment in both AD and strokes patients [139]. Tau bands ranging from 20 to 40 kDa were found in AD and control CSF [140, 141], which corresponded to N-terminal and mid-domain fragments, while no C-terminal fragments were found. Therefore, biomarker-based diagnosis would strongly depend on the subset of tau species analyzed.

Tau fragments have been proposed as biomarkers not only for the discrimination of AD from controls, but also for the differential diagnosis within related neurodegenerative diseases. For instance, a divergent pattern of expression of different N-terminal tau fragments was found between AD and PSP, even though such kind of studies are limited by the frequently overlapping clinical diagnosis [142]. Nonetheless, the ratio between a 33 kDa and a 55 kDa fragment in CSF was proposed as a more specific and reliable biomarker for the diagnosis of PSP [63]. Moreover, in CSF derived from TBI patients, a 30–50 kDa tau fragment was found to correlate with the extent of axonal damage [143]. Lastly, in CSF derived from either lumbar or cervical puncture from amyotrophic lateral sclerosis (ALS) patients the neurotoxic 17 kDa fragment produced by calpain cleavage was found to be elevated compared to controls [144].

While no C-terminal tau fragment was detected in CSF, a combination of ELISA and mass spectrometry analysis [145] revealed the presence of a C-terminal tau fragments in serum derived from AD patients. The levels of this fragment inversely correlated with the Mattis Dementia Rating Scale, suggesting that the increase of the fragment in the serum might parallel the cognitive decline.
