P4‐067: Influence of Cell Bioenergetics on App Processing

Abstract

(1) APOE4 exhibits a loss of function due to the fact that it is poorly lipidated and quickly catabolized (2) APOE4 particles are themselves toxic. During the disease progression Ab exists as monomer, soluble Ab oligomers and fibrillar Ab. There is increasing evidence that Ab oligomers are the most toxic species, contributing to AD related cognitive decline, synaptic dysfunction and inhibition of long-term potentiation. We hypothesize that APOE4 interaction with Ab diminishes the formation of toxic oligomeric species and alleviates its deleterious effects. Methods: Electron microscopy and western and dot blotting were used to characterize complexes, resulting from co-incubating monomeric Ab with APOE3 or APOE4 at oligomer forming conditions. Utilizing primary mouse neuronal cultures we determined the effect of Ab oligomers +/-APOE particles on transcriptome profiles. We also examined the impact of these co-incubations on synaptic markers and structure utilizing Sholl analysis. Lastly, we infused Ab oligomers +/-APOE particles into the hippocampi of WT mice and examined their impact on cognitive performance utilizing novel object recognition and fear conditioning. Results: We demonstrate that ApoE3 and ApoE4 particles decrease Ab oligomer formation. Furthermore , treatment of neurons with APOE-Ab complexes significantly impacts the transcriptome and neuronal structure when compared to Ab oligomers alone. Hippocampal infusion of Ab oligomers significantly decreased cognitive performance in WT mice in two memory paradigms. Lastly, APOE3 and APOE4 when used at equal concentrations are equally protective against deleterious effects of Ab oligomers on cognitive function. Conclusions: This study demonstrates the importance of oligomeric Ab in AD related cogni-tive decline and the ability of APOE to influence oligomeric Ab toxicity. Moreover, this study provides further support of APOE as a potential therapeutic target for AD. Background: We discovered that Ab accumulates in the supranu-clear subregion of the lens in the eyes of people with Alzheimer's Disease (AD) (Goldstein, Lancet, 2003) and Down Syndrome (DS); (Moncaster, PloS One, 2010). Ab interacts with crystallin proteins in the lens to create light scattering aggregates. Crystallin proteins comprise w90% of lens protein in mature lens fiber cells, do not undergo turnover, and thus remain extant throughout life. Crystallins undergo various post-translational modifications during aging that disrupt the normal functioning of the proteins, facilitating aggregation and insolubilization. We expand on previous work in AD and DS and hypothesize that these cumulative alterations in the crystallins in the lens may also constitute an in vivo biomarker of molecular aging for the human body. Methods: Quasi-elastic light scattering (QLS) has previously been used to study the aggregation of lens proteins. QLS tracks time-dependent changes in hydrodynamic radius, polydispersity, and supramolecu-lar order of proteins. Here we use QLS to measure changes in human lens proteins as...