Secreted-APP and holo-APP bind Amyloid beta through distinct domains eliciting different toxic responses on hippocampal neurons.

GABRIELA KEDIKIAN, FLORENCIA HEREDIA, VICTORIA ROZES SALVADOR, DANIEL RAIMUNDA, NORA ISOARDI, LORENA HEREDIA AND ALFREDO LORENZO

JOURNAL OF NEUROSCIENCE RESEARCH

WILEY-LISS, DIV JOHN WILEY & SONS INC

Año: 2010

0360-4012

Amyloid beta (Aâ) is a metabolic product of Amyloid â Precursor protein (APP).  Deposition of Aâ in the brain and neuronal degeneration are characteristic hallmarks of Alzheimer’s disease (AD).  Aâ induces neuronal degeneration, but the mechanism of neurotoxicity remains elusive.  Increasing evidence implicates APP as a receptor-like protein for Aâ fibrils (fAâ).  In this study, we present further experimental support for the direct interaction of APP with fAâ, and for its involvement in Aâ neurotoxicity.  Using recombinant purified holo-APP (h-APP) we showed that it directly binds fAâ.  Employing deletion mutant forms of APP we show that two different sequences are involved in the binding of APP to fAâ.  One sequence in the n-terminus of APP is required for binding of fAâ to secreted-APP (s-APP), but not to h-APP.  In addition, the extracellular juxtamembrane Aâ-sequence mediates binding of fAâ to h-APP, but not to s-APP.  Deletion of the extracellular juxtamembrane Aâ-sequence abolishes abnormal h-APP accumulation and toxicity induced by fAâ deposition, while deletions in the n-terminus of APP does not affect Ab toxicity.  These experiments show that interaction of toxic Aâ-species with its membrane-anchored parental protein promotes toxicity in hippocampal neurons, adding further support to an Aâ-receptor-like function of APP directly implicated in neuronal degeneration in AD.