Tau is essential to β-amyloid-induced neurotoxicity

Abstract

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 ␤-amyloid peptide (A␤); 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 A␤-induced neurite degeneration in central neurons. Cultured hippocampal neurons obtained from wild-type, tau knockout, and human tau transgenic mice were treated with fibrillar A␤. Morphological analysis indicated that neurons expressing either mouse or human tau proteins degenerated in the presence of A␤. On the other hand, tau-depleted neurons showed no signs of degeneration in the presence of A␤. These results provide direct evidence supporting a key role for tau in the mechanisms leading to A␤-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 A␤-mediated neurodegeneration.R ecent research on the field of Alzheimer's disease (AD) has been focused on the mechanisms leading to the formation of senile plaques and neurofibrillary tangles, the two hallmark lesions of this neurodegenerative disease. Both lesions are the result of the pathological deposition of proteins normally distributed throughout the brain. Senile plaques are extracellular deposits of fibrillar ␤-amyloid peptide (A␤), a cleavage product of the amyloid precursor protein (see refs. 1-5 and refs. therein). Neurofibrillary tangles, on the other hand, are intracellular bundles of self-assembled hyperphosphorylated tau proteins (6-10). Although these two lesions are often present in the same brain areas, a mechanistic link between them has yet to be established. Indirect evidence from several studies using cultured neurons suggests a role for tau in the generation of dystrophic neurites in the presence of fibrillar A␤. The common picture emerging from these studies indicates that deposition of fibrillar A␤ induces phosphorylation of tau followed by progressive degeneration of neuronal processes (11-16). In addition, several groups have reported that kinases known to phosphorylate tau in vitro were activated in response to fibrillar A␤ deposition. When young neurons were incubated in the presence of fibrillar A␤, both GSK3␤ and CDK5 were activated (11, 17). In mature hippocampal neurons, on the other hand, fibrillar A␤-induced neurotoxicity was accompanied by the sustained activation of mitogen-activated protein kinase (MAPK) (14)(15)(16)18). Taken collectively, these results suggest a key role for tau in the generation of dystrophic neurites in response to fibrillar A␤ treatments. To obtain direct ev...

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