Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate α-synuclein fibrilization

Abstract

Oxidative stress, inflammation and alpha-synuclein overexpression confer risk for development of alpha-synucleinopathies-neurodegenerative diseases that include Parkinson disease and Lewy body dementia. Dopaminergic neurons undergo degeneration in these diseases and are particularly susceptible to oxidative stress because dopamine metabolism itself creates reactive oxygen species. Intraneuronal deposition of alpha-synuclein as amyloid fibrils or Lewy bodies is the hallmark of these diseases. Herein, we demonstrate that concentrations of oxidative cholesterol metabolites derived from reactive oxygen species are elevated in the cortices of individuals with Lewy body dementia relative to those of age-matched controls, and we show that these metabolites accelerate alpha-synuclein aggregation in vitro. The increase in the production of these cytotoxic cholesterol metabolites is also observed in a dopaminergic cell line that overexpresses alpha-synuclein. By extension, these data lead to the hypothesis that oxidative stress produces cholesterol aldehydes that enable alpha-synuclein aggregation, leading to a pathologic cycle.

Alpha-Synuclein and the Immune Response in Parkinson’s Disease

“…Oxidation (Ko et al, 2000;Souza et al, 2000) and nitration (Giasson et al, 2000;Souza et al, 2000) of Syn, in turn, can lead to the formation of more aggregates, which could result in increased cytotoxic effects. Consistent with this, Kelly et al have shown that high levels of oxidized cholesterol metabolites in brains from PD and dementia with LB patients, accelerate Syn fibrillation (Bosco et al, 2006). On the other hand, McGeer and colleagues (Klegeris et al, 2007a) have reported that Syn-stimulated microglia, in combination with IFN-, produce and increase in the toxicity on human monocytic cells exerted by neurotoxic secretions (Klegeris et al, 2007a).…”

Site-specific modification of Alzheimer's peptides by cholesterol oxidation products enhances aggregation energetics and neurotoxicity

“…Prior data indicated that cholesterol oxidation products 1 and 2, denoted 1(2) hereafter because they interconvert via an aldol/retro-aldol reaction (16,18,24), react with A␤ via Schiff base formation at the N-terminal ␣-amine of Asp-1 (D1) and the side-chain -amines of Lys-16 (K16) and Lys-28 (K28) (18). Compounds 1 and 2 have been detected by us (18,28) and others (29) in ex vivo human and rat brain samples at combined concentrations of up to 400 pg/mg of wet brain (Ϸ1 M concentration). Scheinost et al (27) recently suggested that K16 is the ''hot spot'' for A␤ aggregation induced by 1(2) modification.…”

Neurodegeneration-associated instability of ribosomal DNA.

“…Interestingly, alterations in both of these areas are common to both Alzheimer's disease and Dementia with Lewy Bodies [52,[72][73][74].…”