Cholesterol in the Pathogenesis of Alzheimer’s, Parkinson’s Diseases and Autism: Link to Synaptic Dysfunction

Abstract

In our previous review, we described brain cholesterol metabolism in control conditions and in the case of some rare neurological pathologies linked to defects in the genes which are directly involved in the synthesis and/or traffic of cholesterol. Here, we have analyzed disruptions in cholesterol homeostasis in widespread neurodegenerative diseases (Alzheimer’s and Parkinson’s diseases) and autism spectrum disorders. We particularly focused on the synaptic dysfunctions that could arise from changes in both membrane cholesterol availability and oxysterol production. Notably, alterations in the brain cholesterol metabolism and neurotransmission occur in the early stages of these pathologies and the polymorphism of the genes associated with cholesterol homeostasis and synaptic communication affects the risk of onset and severity of these diseases. In addition, pharmacological and genetic manipulations of brain cholesterol homeostasis in animal models frequently have marked effects on the progression of neurodegenerative diseases. Thus, the development of Alzheimer’s, Parkinson’s and autism spectrum disorders may be partially associated with an imbalance of cholesterol homeostasis that leads to changes in the membrane cholesterol and oxysterol levels that, in turn, modulates key steps in the synaptic transmission.

Tau-Cofactor Complexes as Building Blocks of Tau Fibrils

“…that dictates the tau fold and packing that constitutes the structure of the final aggregate. In a cellular context, this hypothesis suggests that a given strain could be created/propagated when tau comes in contact with a specific cofactor [e.g., promoted by tau mislocalization (Thies and Mandelkow, 2007;Hoover et al, 2010) or abnormal homeostasis (Petrov et al, 2017)]. In addition, we highlighted here that taucofactor complexes can be isolated in vitro, and shown to only convert to fibrils when exposed to a potent seed.…”

Na+, K+‐ATPase activity in children with autism spectrum disorder: Searching for the reason(s) of its decrease in blood cells

“…We observed a decrease of plasma membrane cholesterol in the erythrocytes from ASD children, thus confirming a previous finding by Schengrund, Ali‐Rahmani, and Ramer [], who also observed a decrease in monosialotetrahexosylganglioside (GM1) content, and no difference in phosphatidylcholine and phosphatidylserine content. Petrov, Kasimov, and Zefirov [] recently pointed out that cholesterol dysfunctions have been detected in many neurodegenerative disorders, however neither Schengrund’ or Petrov’ groups related these findings to NKA activity. Membrane lipid moiety plays a very important regulatory role on NKA, as pointed out by Cornelius et al [] and Habeck et al [], who in particular draw attention to cholesterol and phosphatidylserine for their stabilization roles and to sphingomyelin and phosphatidylcholine for their inhibitory functions.…”

Soluble Epoxide Hydrolase and Brain Cholesterol Metabolism

“…Disruptions in cholesterol metabolism are significantly associated with AD pathogenesis, even though it is uncertain if these are a cause or a consequence of the disease (Petrov et al, 2017). The efflux of oxysterols from the brain into the blood plays a key role in this process (Loera-Valencia et al, 2019).…”