Dissecting Toxicity of Tau and beta-Amyloid

Background: How beta-amyloid (A beta) and tau exert toxicity in Alzheimer's disease is only partly understood. Major questions include (1) which aggregation state of A beta confers toxicity, (2) do amyloidogenic proteins have similar mechanisms of toxicity, and (3) does soluble tau interfere with cellular functions? Methods: To determine A beta toxicity in P301L mutant tau transgenic mice, mitochondrial function was assessed after insult with monomeric, oligomeric and fibrillar A beta. Amylin and A beta toxicity were compared in cortical and hippocampal long-term cultures. To determine tau toxicity, K369I mutant tau mice were established as a model of frontotemporal dementia, analyzed biochemically and compared with human diseased brain. Results: Oligomeric and fibrillar A beta 42 were both toxic, although to different degrees. Human amylin shared toxicity with A beta 42, an effect not observed for nonamyloidogenic rat amylin. Clinical features of K369I tau mice were caused by aberrant interaction of phosphorylated tau with JIP1, a component of the kinesin transport machinery. Conclusion: Our data support the notion of a synergistic action of tau and A beta pathology on mitochondria. A specific conformation of A beta 42 and human amylin determines toxicity. Finally, trapping of JIP1 by phosphorylated tau in the neuronal soma emerges as a fundamental pathomechanism in neurodegeneration. Copyright (C) 2010 S. Karger AG, Basel