A COMPLEX CASCADE OF PRODUCTION AND DEGRADATION DETERMINES THE YIELD OF AΒ YIELD IN VIVO

Kumar Sambamurti, Vasudevaraju Padmaraju, Panneerselvam Chinnakannu, Debomoy K. Lahiri, Nigel H. Greig and Sumit Sarkar

Medical University of South Carolina, Charleston, SC, USA

Abstract

The Alzheimer amyloid β protein (AB) deposit remains the best target associated with Alzheimer Disease (AD). However, a number of failed clinical trials indicate that inhibition of Aβ production in its last production step γ-secretase (GS)-- actually worsen rather than improve disease outcome. We have previously shown that GS increases the yield of AB at low doses and only reduces it at high levels. We have treated mice with a GS inhibitor (GSI) to examine its effects in vivo and find that AB levels are increased in the brain as well. This change appears to be a complex effect of AB production and degradation. Moreover, DAPT treatment results in changes in retinal function consistent with a key function of this enzyme in neuronal maintenance. We propose that preserving GS function is critical for prevention of AD. GS is important in maintaining vascular permeability and therefore plays a pleiotropic role in neuroprotection. Moreover, we have generated mice expressing both AB and microtubule-associated protein τ (MAPT) that deposit plaques and tangles at a young age of ~6 months. These mice perform more poorly in memory tasks than mice depositing plaques or tangles alone.