Amyloid beta (Aβ) is a metabolic product of Amyloid β Precursor protein(APP).  Deposition of Aβ in the brain andneuronal degeneration are characteristic hallmarks of Alzheimer?s disease(AD).  Aβ induces neuronal degeneration,but the mechanism of neurotoxicity remains elusive.  In this presentation, we will show cellularand molecular evidence for the involvement of APP in the mechanism of neuronaldegeneration elicited by Aβ.  Byoverexpressing different mutant forms of APP into primary hippocampal neuronsin vitro we show that Aβ interacts with APP and triggers a Go-dependentsignaling cascade that promotes neuronal death. Importantly, we will also present novel evidence indicating that therecently discovered mutation in APP intracellular domain (APPH733P) confers resistanceto Aβ-induced neurodegeneration suggesting that it might reduce the risk of ADon its carriers.

Our datasuggest that APP plays a critical role in neuronal disfunction in AD beyond itswell established participation as the only source of Aβ.