Background: How β-amyloid (Aβ) and tau exert toxicity in Alzheimer’s disease is only partly understood. Major questions include (1) which aggregation state of Aβ confers toxicity, (2) do amyloidogenic proteins have similar mechanisms of toxicity, and (3) does soluble tau interfere with cellular functions? Methods: To determine Aβ toxicity in P301L mutant tau transgenic mice, mitochondrial function was assessed after insult with monomeric, oligomeric and fibrillar Aβ. Amylin and Aβ 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 Aβ42 were both toxic, although to different degrees. Human amylin shared toxicity with Aβ42, 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 Aβ pathology on mitochondria. A specific conformation of Aβ42 and human amylin determines toxicity. Finally, trapping of JIP1 by phosphorylated tau in the neuronal soma emerges as a fundamental pathomechanism in neurodegeneration.

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