The Role of High-Density Lipoproteins and Related Pathways in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is the most prevalent age-related dementia and will place an increasingly demanding burden on our healthcare system as the population ages. It has been firmly established that high plasma levels of high-density lipoprotein (HDL) protect against cardiovascular disease and accumulating evidence indicates that the beneficial role of HDL extends to the central nervous system. There are several important biological mechanisms that regulate HDL generation and metabolism/function. One is through the cholesteryl ester transfer protein (CETP), which transports cholesterol esters and triglycerides between different lipoprotein particles. Loss-of-function mutations in CETP are associated with better cognition in aging. To investigate the role of CETP in AD, human CETP transgenic mice were crossed with an Alzheimer’s mouse model, followed by biochemical and behavioral analyses. The results showed that CETP-induced modest decrease in plasma HDL levels was insufficient to affect brain amyloid pathology, neuroinflammation, or memory function. Next, to explore the therapeutic potential of a cardiovascular protective, HDL-mimetic-peptide called D-apoJ[113-122], AD mice were treated with the peptide. This treatment robustly reduced brain amyloid pathology and improved memory function in AD mice. Further analyses showed that D-apoJ[113-122] exerted its beneficial effects through reduction of cerebral vascular amyloid deposition and clearance of brain amyloid to plasma. Finally, prenyltransferase-deficient mice were used to investigate the role of protein prenylation in synaptic function. Prenylation is an important posttranslational lipid modification process that attaches isoprenoids (the intermediates in the cholesterol biosynthesis pathway) to target proteins. Electrophysiological/histochemical experiments showed that systemic or forebrain-specific deficiency of one particular prenyltransferase, geranylgeranyltransferase-1, caused marked impairment in hippocampal synaptic plasticity and decrease in neuronal dendritic spine density. Further analyses indicated that reduction of prenylation of certain small GTPases, which rely on prenylation for proper cellular localization and function, underlies the detrimental effects in these mice, as observed in aged mouse brains. These results corroborate the critical role of protein prenylation in synaptic function during development and in the adult brain. Taken together, findings from this research provide novel insights into the role of HDL and related pathways in the pathogenesis of AD, and offer new avenues to develop effective therapies for AD.