Role of LDL cholesterol and endolysosomes in amyloidogenesis and Alzheimer's disease.

Abstract

The pathogenesis of late-onset sporadic Alzheimer's disease (AD) is believed to result from complex interactions between nutritional, environmental, epigenetic and genetic factors. Among those factors, altered circulating cholesterol homeostasis, independent of the APOE genotype, continues to be implicated in brain deposition of amyloid beta protein (Aβ) and the pathogenesis of AD. It is believed that trafficking of amyloid beta precursor protein (AβPP) into endolysosomes appears to play a critical role in determining amyloidogenic processing of AβPP because this is precisely where two enzymes critically important in AβPP metabolism are located; beta amyloid converting enzyme (BACE-1) and gamma secretase enzyme. We have shown that elevated levels of LDL cholesterol promote AβPP internalization, disturb neuronal endolysosome structure and function, and increase Aβ accumulation in neuronal endolysosomes. Here, we will further discuss the linkage between elevated levels of LDL cholesterol and AD pathogenesis, and explore the underlying mechanisms whereby elevated levels of plasma LDL cholesterol promote amyloidogenesis.