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.

Domain 4 (D4) of Perfringolysin O to Visualize Cholesterol in Cellular Membranes—The Update

“…In addition, the distribution of cholesterol between the exofacial leaflets and cytosolic leaflets of the PM is still debatable (see Section 2.5). From the patho-physiological standpoint, numerous studies have shown that cholesterol in the PM has crucial functions in cell signalling, endocytosis, bacterial/viral infection, cancer, angiogenesis, and Alzheimer’s disease [21,22,23,24,25,26]. Furthermore, cholesterol regulates the recycling pathway, which is consistent with enrichment of cholesterol in REs [5,27,28,29,30,31,32].…”

Chronic psychological stress and high-fat high-fructose diet disrupt metabolic and inflammatory gene networks in the brain, liver, and gut and promote behavioral deficits in mice

“…This change persisted two weeks beyond the psychological stress exposure. Some studies suggest that cholesterol changes influence neurological disorders associated with protein aggregation like prion disease and Alzheimer’s disease-related dementia (Hannaoui et al, 2014). In light of this connection, our findings suggest that further investigations of the interactions between stress and HFHF consumption on cholesterol metabolism could shed new insight into the relationship between cardiovascular disease, MetS, cognitive decline, and dementia.…”

Efficient inhibition of infectious prions multiplication and release by targeting the exosomal pathway

“…It was recently reported that HRS depletion affects cholesterol trafficking and leads to its accumulation in LE/ LY [53]. Interestingly, cholesterol was previously well characterized as a key factor involved in the conversion of PrP C into PrP Sc (for review [19]). Perturbation of cholesterol synthesis and trafficking prevents prion conversion or its degradation.…”

“…Although PrP res (the PK-resistant form of PrP Sc ) is tightly associated with prion infectivity, PK-sensitive PrP Sc might be infectious as well [15]. The mechanisms that initiate the conversion of PrP C into its pathological isoform are still not fully understood but metabolism and trafficking of cholesterol were found both to play pivotal roles in prion conversion and/or degradation [16][17][18][19][20]. Both PrP C and PrP Sc isoforms are associated with lipid rafts/membrane microdomains (DRMs) enriched in cholesterol and sphingolipids [20][21][22] and preventing PrP C raft association or destabilization of rafts by cholesterol depletion blocks PrP C to PrP Sc conversion [19,23].…”