title: Role of endolysosomes and cholesterol in the pathogenesis of Alzheimer's disease: Insights into why statins might not provide clinical benefit.
abstract: Altered cholesterol homeostasis in general and increased levels of low-density lipoprotein (LDL) cholesterol specifically is a robust risk factor for the pathogenesis of sporadic Alzheimer's disease (AD). Because of this, the family of drugs known as statins have been tried extensively to lower cholesterol levels in attempting to prevent and/or lessen the neuropathogenesis of AD. Unfortunately, evidence accumulated to date is insufficient to support the continued use of statins as a viable pharmacotherapeutic approach against AD. To understand these complex and inter-related issues it is important to review how altered cholesterol homeostasis contributes to AD pathogenesis and why statins have not provided clinical benefit against AD. Apolipoproteins with their different affinities for various lipids and the receptors that control cholesterol uptake can result in drastic differences in cholesterol trafficking into and its distribution within neurons. The presence of the apoE4 or elevated plasma levels of LDL cholesterol can lead to a set of conditions that resembles lysosomal lipid storage disorders observed in Niemann-Pick type C disease such as impaired recycling of cholesterol back to the endoplasmic reticulum (ER), Golgi and plasma membranes, cholesterol deficiencies in plasma membranes, and increased cholesterol accumulation in endolysosomes resulting in endolysosome dysfunction. Consequently, the use of statins to block cholesterol synthesis in ER might not only decrease further plasma membrane cholesterol levels thus disturbing synaptic integrity, but also could also increase cholesterol burden in endolysosomes thus worsening endolysosome dysfunction. Therefore, it is not surprising that the use of cholesterol-lowering strategies with statins has not resulted in clinical benefit for patients living with AD.
authors: Department of Basic Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58203.
authors: Xuesong
authors: X
authors: Chen
authors: Department of Basic Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58203.
authors: Liang
authors: L
authors: Hui
authors: Department of Basic Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58203.
authors: Jonathan D
authors: JD
authors: Geiger
keywords: Alzheimer’s disease; ApoE4; LDL cholesterol; endolysosome dysfunction; lysosomal lipid storage disorders; statins