Senile plaques and neurofibrillary tangles, the two hallmark lesions of Alzheimer's disease, are the results of the pathological deposition of proteins normally present throughout the brain. Senile plaques are extracellular deposits of fibrillar β-amyloid peptide (Aβ); neurofibrillary tangles represent intracellular bundles of self-assembled hyperphosphorylated tau proteins. Although these two lesions are often present in the same brain areas, a mechanistic link between them has yet to be established. In the present study, we analyzed whether tau plays a key role in fibrillar Aβ-induced neurite degeneration in central neurons. Cultured hippocampal neurons obtained from wild-type, tau knockout, and human tau transgenic mice were treated with fibrillar Aβ. Morphological analysis indicated that neurons expressing either mouse or human tau proteins degenerated in the presence of Aβ. On the other hand, tau-depleted neurons showed no signs of degeneration in the presence of Aβ. These results provide direct evidence supporting a key role for tau in the mechanisms leading to Aβ-induced neurodegeneration in the central nervous system. In addition, the analysis of the composition of the cytoskeleton of tau-depleted neurons suggested that the formation of more dynamic microtubules might confer resistance to Aβ-mediated neurodegeneration.