Guedjdal, S.; Leghay, C.; Derisbourg, M.; Eddarkaoui, S.; Lecerf, S.; Vermon, F.; Caillierez, R.; Begard, S.; Regost, C.; Laloux, C.; da Costa, P. J.; Carvalho, K.; Chiappetta, G.; Verdier, Y.; Buee-Scherrer, V.; Deramecourt, V.; Schraen, S.; Blum, D.; MARTIN, F.; Buee, L.; Hamdane, M.

Neurodegenerative diseases like Alzheimer disease (AD) are characterized by progressive accumulation of pathological Tau proteins. Among the diverse Tau species, truncated variants are emerging as key contributors, yet their identity remains elusive, particularly for the N-terminal truncated ones. The present study identifies and characterizes a novel N-terminally truncated and N-alpha-acetylated form of the Tau protein. Using a newly developed antibody specifically targeting this truncated variant, we demonstrate that this species accumulates early in degenerating neurons in both transgenic mouse models of AD-related Tau pathology and post-mortem brain tissues from AD patients. Importantly, in vivo functional experiments reveal that expression of this truncated Tau species exacerbates Tau pathology, whereas targeted immunotherapeutic with the specific antibody significantly reduces pathological Tau accumulation and prevents associated memory impairments. These findings position this newly identified Tau variant as both a marker of neurofibrillary degeneration and a pathogenic driver of neurodegeneration and supports its potential as a therapeutic target in Tau-related disorders, notably AD.