Cholesterol balance in prion diseases and Alzheimer's disease

Abstract

Prion diseases are transmissible and fatal neurodegenerative disorders of humans and animals. They are characterized by the accumulation of PrPSc, an aberrantly folded isoform of the cellular prion protein PrPC, in the brains of affected individuals. PrPC is a cell surface glycoprotein attached to the outer leaflet of the plasma membrane by a glycosyl-phosphatidyl-inositol (GPI) anchor. Specifically, it is associated with lipid rafts, membrane microdomains enriched in cholesterol and sphinoglipids. It has been established that inhibition of endogenous cholesterol synthesis disturbs lipid raft association of PrPC and prevents PrPSc accumulation in neuronal cells. Additionally, prion conversion is reduced upon interference with cellular cholesterol uptake, endosomal export, or complexation at the plasma membrane. Altogether, these results demonstrate on the one hand the importance of cholesterol for prion propagation. On the other hand, growing evidence suggests that prion infection modulates neuronal cholesterol metabolism. Similar results were reported in Alzheimer's disease (AD): whereas amyloid β peptide formation is influenced by cellular cholesterol, levels of cholesterol in the brains of affected individuals increase during the clinical course of the disease. In this review, we summarize commonalities of alterations in cholesterol homeostasis and discuss consequences for neuronal function and therapy of prion diseases and AD.

Figure 1

Cholesterol metabolism, lipid rafts and cellular prion propagation. (I) Cellular cholesterol, an essential component of lipid rafts, is synthesized from cholesterol precursors, with HMGCR as the rate limiting enzyme in the ER membrane; (II) Synthesized Cholesterol is secreted in an ABCA1 dependent process to form lipoprotein particles, or it is incorporated into membranes of the secretory pathway, where lipid rafts are assembled in the trans-Golgi network; (III) Uptake of extracellular cholesterol is mediated by ApoE/HDL interaction with the LDL-receptor. Cholesterol dissociates from the lipoprotein, is de-esterified and exported from late endosomes in a NPC protein dependent manner. It is then either transported to the plasma membrane or adds to the regulatory pool which prevents cleavage and nuclear translocation of SREBP. Once the capacity of cells to absorb cholesterol is exceeded, cholesterol is, in a small part, esterified by ACAT and accumulated as cytosolic lipid droplets (IV); The major pool of excess cholesterol is hydroxylated by CYP46 and converted to 24S-hydroxycholesterol, crosses the BBB and diffuses into the blood circulation (V). The red dotted lines represent examples for interference in cholesterol metabolism that resulted in a reduction or clearance of cellular PrP^Sc accumulation.