Identificazione di un frammento N-terminale della proteina tau generato dal taglio delle caspasi apoptotiche in modelli cellulari ed animali del morbo di Alzheimer

Biochemical modifications of tau proteins have been proposed to be among the earliest neurobiological changes in Alzheimer’s disease (AD) and correlate better with cognitive symptoms than do beta-amyloid plaques. We have recently reported that adenovirus-mediated overexpression of the NH2 26-230aa tau fragment evokes a potent NMDA-mediated neurotoxic effect in primary neuronal cultures. In order to assess whether such N-terminal tau fragment(s) are indeed produced during apoptosis or neurodegeneration in vivo, we attempted to ascertain their presence in cell and animal models using an anti-tau antibody directed against the N-terminal sequence of human protein located downstream of the caspase(s) cleavage site DRKD25-QGGYTMHQDQ. We provide biochemical evidence that a caspase(s)-cleaved NH2-terminal tau fragment of 20-22 kDa, consistent with the size of the NH2 26-230aa neurotoxic fragment of tau, is generated in vitro in differentiated human SH-SY5Y cells undergoing apoptosis by BDNF withdrawal or following treatment with staurosporine. In addition this NH2-terminally cleaved tau fragment, whose expression correlates with a significant up-regulation of caspase(s) activity, is also specifically detected in vivo in the hippocampus of 15 months old AD11 transgenic mice, a model in which a progressive AD-like neurodegeneration is induced by the expression of transgenic anti NGF antibodies. Having confirmed that adenovirus-mediated overexpression of NH2-tau fragment lacking the first 25 aminoacids evokes a potent neurotoxic effect, sustained by protracted stimulation of NMDA receptors, in primary neuronal cultures we investigated whether and how chemically synthesized NH2-derived tau peptides, i.e. NH2-26–44 and NH2-1–25 fragments, affect mitochondrial function. Oxidative phosphorylation is not affected by NH2-1–25 tau fragment, but dramatically impaired by NH2-26–44 tau fragment. Both cytochrome c oxidase and the adenine nucleotide translocator are targets of NH2-26–44 tau fragment, but adenine nucleotide translocator is the unique mitochondrial target responsible for impairment of oxidative phosphorylation by the NH2-26–44 tau fragment, which then exerts deleterious effects on cellular availability of ATP synthesized into mitochondria. The results (Corsetti et al., 2008; Atlante et al., 2000) support the idea that aberrant activation of caspase(s), following apoptotic stimuli or neurodegeneration insults, may produce one or more toxic NH2-tau fragments, that further contribute to propagate and increase cellular dysfunctions in AD.