Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease

Abstract

Alzheimer's disease (AD) is an age-related disorder characterized by deposition of amyloid ␤-peptide (A␤) and degeneration of neurons in brain regions such as the hippocampus, resulting in progressive cognitive dysfunction. The pathogenesis of AD is tightly linked to A␤ deposition and oxidative stress, but it remains unclear as to how these factors result in neuronal dysfunction and death. We report alterations in sphingolipid and cholesterol metabolism during normal brain aging and in the brains of AD patients that result in accumulation of long-chain ceramides and cholesterol. Membrane-associated oxidative stress occurs in association with the lipid alterations, and exposure of hippocampal neurons to A␤ induces membrane oxidative stress and the accumulation of ceramide species and cholesterol. Treatment of neurons with ␣-tocopherol or an inhibitor of sphingomyelin synthesis prevents accumulation of ceramides and cholesterol and protects them against death induced by A␤. Our findings suggest a sequence of events in the pathogenesis of AD in which A␤ induces membrane-associated oxidative stress, resulting in perturbed ceramide and cholesterol metabolism which, in turn, triggers a neurodegenerative cascade that leads to clinical disease.amyloid ͉ apoptosis ͉ hippocampus ͉ lipid peroxidation ͉ sphingomyelin C hanges that occur in the brain during aging increase the risk of Alzheimer's disease (AD), a disorder involving the progressive deposition of amyloid ␤-peptide (A␤) and associated degeneration of neurons in brain regions involved in learning and memory (1). Two factors that are believed to contribute to neuronal dysfunction and degeneration in AD are increased oxidative stress and increased production of neurotoxic forms of A␤ (2). Alterations in lipid metabolism may also play roles in AD because the risk of AD is affected by inheritance of different isoforms of apolipoprotein E (3), changes in cholesterol metabolism can affect A␤ production in cell culture and in vivo (4-6), and drugs that lower cholesterol levels may reduce the risk of AD (7,8). However, a direct link between alterations in the metabolism of cholesterol and other membrane lipids in AD has not been established, and it is not known whether and how such lipid alterations might lead to neuronal dysfunction and death.Membrane microdomains that are rich in cholesterol and sphingolipids play important roles in various cellular signaling pathways (9, 10). Sphingomyelin is a major source of ceramides, lipid mediators that are generated when sphingomyelin is cleaved by sphingomyelinases, enzymes activated by inflammatory cytokines (11) and oxidative stress (12). Ceramides play important roles in regulating an array of physiological processes, including cell proliferation and differentiation, and a form of programmed cell death called apoptosis (13). Ceramides have been implicated in the pathological death of neurons that occurs in ischemic stroke (14) and Parkinson's disease (15). In the present study, we document significant increases in levels of m...

Alzheimer's disease–like pathology has transient effects on the brain and blood metabolome

“…SPHs are precursors for ceramide production. Their accumulation induces apoptosis and seems to worsen neurodegeneration by increasing Aβ biosynthesis and promoting gamma-secretase processing of APP (Cutler et al, 2004;Grimm et al, 2005;Puglielli et al, 2003). Our findings closely resemble other work showing that global brain levels of ceremides, sphingolipids and related molecules are increased in the cerebral cortex of APP SL /PS1Ki and APP/PS1 mice especially after the age of 6 months (Barrier et al, 2010).…”

Deregulation of sphingolipid metabolism in Alzheimer's disease

“…Aging results in the accumulation of various stress factors, including pro-inflammatory and oxidative stress molecules that can stimulate sphingomyelinase activities, leading to the production of the pro-apoptotic lipid, ceramide (Cutler et al, 2004;Joseph et al, 2000). Alzheimer's disease is the most common form of age-related dementia, characterized by the accumulation of Aβ peptides in the brain.…”

“…Ceramide is an important second messenger molecule that regulates diverse cellular processes including cell growth, differentiation, and apoptosis. Ceramide levels also increase in response to aging and various age-related stress factors (e.g., oxidative stress), and are directly involved in apoptotic signaling in various cell types, including neurons (Costantini et al, 2005;Cutler et al, 2004;Kolesnick and Kronke, 1998;Perez et al, 2005). Furthermore, ceramide stabilizes the APP cleaving enzyme 1 (BACE1), promoting Aβ biogenesis (Patil et al, 2007;Puglielli et al, 2003), and reduction of ceramide levels leads to reduced secretion of APP and Aβ in human neuroblastoma cells (Tamboli et al, 2005).…”

“…For example, the total phospholipid and sulfatide content in AD was decreased as compared to normal (Cheng et al, 2003;Gottfries et al, 1996;Han et al, 2002;Pettegrew et al, 2001;Soderberg et al, 1992), while the ceramide and cholesterol levels were elevated (Cutler et al, 2004;Han et al, 2002). Satoi et al found that the ceramide levels in the cerebrospinal fluid (CSF) also were increased in patients with AD (Satoi et al, 2005), and we recently reported that the level and activity of acid ceramidase (AC) was elevated as well, perhaps in response to the elevated ceramide (Huang et al, 2004).…”

Lipid Droplets: Their Role in Nanoparticle-Induced Oxidative Stress

“…50,58 Lipid droplets are currently considered to be metabolically active organelles, and their behavior in stressed cells is intriguing, as lipid metabolism is impaired during oxidative stress. 59,60 Only very limited information is available for communications between lysosomes and LD. Liu et al identified proteins that are common between LD and lysosomes, such as Rab7 and SNAP, suggesting a possible link between these organelles.…”