DELAYED SYNAPTOGENESIS BY THE BETA-AMYLOID PEPTIDE IN THE ADULT BRAIN.

NICOLAS A. MORGENSTERN; GABRIELA LOMBARDI; ALEJANDRO F SCHINDER

Buenos Aires

Simposio; International Symposium on Stem Cell; 2009

ISSRC

Clinical hallmarks of Alzheimer´s disease (AD) have been related to extracellular deposits of Beta-amyloid peptide (ABeta) in the cerebral cortex and hippocampus as amyloid plaques. ABeta peptide is the cleavage product by beta and gamma secretase of a bigger transmembrane protein known as the amyloid precursor protein (APP). Although AD was described more than 100 years ago, its pathogenic mechanism remains unclear.  In humans and animal models of AD, cognitive decline becomes evident much earlier than amyloid plaque formation. There is also evidence of dendritic spine abnormalities in a variety of mental retardation syndromes. In this work we propose that the ABeta peptide affects synapse formation, and this mechanism is responsible for the early cognitive alterations seen in AD.  We use adult neurogenesis to study the effects of ABeta on de novo synaptogenesis by retrovirally traducing APP and/or reporter proteins in newborn neurons of the adult hippocampus in two different models:1- Transgenic mice Tg2576 express the Swedish mutation of APP, which produces elevated levels of ABeta across the brain.  In order to observe the degree of excitatory inputs that newborn neurons reach in this context we are studying dendritic spine density in young and old animals. Preliminary results show no differences in spine density at any of the studied groups.2-APP overexpresion in neurons of wild type mice for studying the cell-autonomous effects of ABeta.  In this model we are currently performing electrophysiological recordings to monitor the function and integration of these neurons at different developmental stages.  Preliminary results show a putative delay in the development and integration of neurons infected with an amylidogenic construction.