Lipid Alterations in Lipid Rafts from Alzheimer's Disease Human Brain Cortex

Martín, M.V.; Fabelo, Noemí; Santpere, Gabriel; Puig, Berta; Marín, Raquel; Ferrer, Isidre; Dı́az, Mario

doi:10.3233/jad-2010-1242

Cited by 241 publications

(227 citation statements)

References 69 publications

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Section: Role Of Fatty-acid Metabolism In Ad Pathogenesissupporting

confidence: 57%

“…In contrast, arachidonic acid increases Aβ production and the formation of amyloid plaques and other neuropathology [91] . Some studies have confirmed the animal results and shown decreased levels of PUFAs and MUFAs in the AD brain [107] .However, there are reports showing that PUFAs do not change significantly in the AD brain compared to the healthy brain [108] . In addition, overexpression of Fat-1, enhancing endogenous production of n-3 PUFAs, in 3×Tg-AD mice significantly reduces phosphorylated tau and improves brain function [106] .…”

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confidence: 53%

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Lipid metabolism in Alzheimer’s disease

Liu

Zhang

2014

Neurosci. Bull.

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Lipids play crucial roles in cell signaling and various physiological processes, especially in the brain. Impaired lipid metabolism in the brain has been implicated in neurodegenerative diseases, such as Alzheimer's disease (AD), and other central nervous system insults. The brain contains thousands of lipid species, but the complex lipid compositional diversity and the function of each of lipid species are currently poorly understood. This review integrates current knowledge about major lipid changes with the molecular mechanisms that underlie AD pathogenesis. Keywords: brain aging; lipid metabolism; Alzheimer's disease ·Review· IntroductionLipids are abundant in the brain. These lipids consist of glycerophospholipids (GPs), sphingolipids, and cholesterol in roughly equimolar proportions [1] . The brain contains about 20% of the total body cholesterol [2] . Cholesterol is primarily derived from local synthesis, whereas uptake of lipoprotein particle-derived cholesterol from the peripheral circulation is usually prevented by the blood-brain-barrier. Lipids, especially cholesterol, have recently been extensively studied in many neurodegenerative diseases. Impairment of cholesterol metabolism (synthesis, transport, and utilization by neurons) in the brain is linked to Alzheimer's disease (AD) and the aging process. In addition, lipid oxidation products accumulate at high levels in aging tissues in mice [3] . Recent studies have demonstrated the important role of altered metabolism in AD [4] . Sphingomyelinases promote apoptosis in human primary neurons through the generation of a proapoptotic molecule, ceramide [5] .Moreover, upregulated arachidonic acid metabolism has been reported in hAPP-J20 AD mice as well as in the AD brain, particularly in regions having high densities of senile plaques with activated microglia [6,7] . Although the potential link between cholesterol and AD pathogenesis has been intensively studied, growing evidence suggests that other lipids, such as sphingolipids and GPs, also play an important role. Here, we review some recent advances in understanding the role lipids play in the aging process and AD pathogenesis. Major Lipid Classes and Functions in the BrainAlthough most lipids serve as structural lipids in cell membranes, they are also directly involved in membrane trafficking, intracellular architecture, and the regulation of proteins and sub-compartments in membranes (lipid rafts) (Table 1). Eukaryotic organisms might contain a dozen major lipid classes, each comprising hundreds of individual molecular species [8] . Lipids have the potential to generate 9 000-100 000 molecular species [9,10] , and a mammalian cell may contain 1 000-2 000 [11] . The brain is one of the most lipid-enriched organs, containing several major classes, such as cholesterol, GPs, sphingolipids and fatty acids [12] . The biological significance of the compositional complexity of lipids is poorly understood. However, the recent development of the shot-gun lipidomics technique may provide more sensitive and quant...

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Section: Role Of Fatty-acid Metabolism In Ad Pathogenesissupporting

confidence: 57%

supporting

confidence: 53%

Lipid metabolism in Alzheimer’s disease

Liu

Zhang

2014

Neurosci. Bull.

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“…Lipid raft fractions from cortical gray matter were isolated following the protocol described by Mukherjee et al (30) with slight modifications (28). Briefly, 0.1 g frontal cortex gray matter was homogenized at 4°C in 8 vol of isolation buffer (50 mmol/L Tris-HCl, pH 8.0, 10 mmol/L MgCl 2 , 20 mmol/L NaF, 1 mmol/L Na 3 VO 4 , 5 mmol/L β-mercaptoethanol and 1 mmol/L PMSF) and a cocktail of protease inhibitors (Roche Diagnostics, Barcelona, Spain) containing 1% Triton X-100 and 5% glycerol in a glass homogenizer for 5 min and then centrifuged at 500g for another 5 min.…”

Section: Lipid Raft Isolationmentioning

confidence: 99%

“…Their alterations have been associated with altered neuronal function, synaptic transmission and neurotransmitter signaling (17,(25)(26)(27). We have recently demonstrated that lipid composition, in particular, long-chain polyunsaturated fatty acids (LCPUFAs), are profoundly altered in the frontal cortex of late stages of Alzheimer's disease (28), which presumably would underlie, at least in part, neuronal dysfunction and cognitive deterioration. However, potential alterations in the lipid structure and spatial organization of lipid rafts in PD have not been explored to date.…”

Section: Introductionmentioning

confidence: 99%

Severe Alterations in Lipid Composition of Frontal Cortex Lipid Rafts from Parkinson’s Disease and Incidental Parkinson’s Disease

Fabelo

Martín

Santpere

et al. 2011

Mol Med

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Lipid rafts are cholesterol-and sphingomyelin-enriched microdomains that provide a highly saturated and viscous physicochemical microenvironment to promote protein-lipid and protein-protein interactions. We purified lipid rafts from human frontal cortex from normal, early motor stages of Parkinson's disease (PD) and incidental Parkinson's disease (iPD) subjects and analyzed their lipid composition. We observed that lipid rafts from PD and iPD cortices exhibit dramatic reductions in their contents of n-3 and n-6 long-chain polyunsaturated fatty acids, especially docosahexaenoic acid (22:6-n3) and arachidonic acid (20:4n-6). Also, saturated fatty acids (16:0 and 18:0) were significantly higher than in control brains. Paralleling these findings, unsaturation and peroxidability indices were considerably reduced in PD and iPD lipid rafts. Lipid classes were also affected in PD and iPD lipid rafts. Thus, phosphatidylserine and phosphatidylinositol were increased in PD and iPD, whereas cerebrosides and sulfatides and plasmalogen levels were considerably diminished. Our data pinpoint a dramatic increase in lipid raft order due to the aberrant biochemical structure in PD and iPD and indicate that these abnormalities of lipid rafts in the frontal cortex occur at early stages of PD pathology. The findings correlate with abnormal lipid raft signaling and cognitive decline observed during the development of these neurodegenerative disorders.

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“…While plaques and tangles are hallmarks of the disease, other apparently unrelated laboratory abnormali-ties are routinely detected in patients, including elevated cholesterol [4], altered fatty acid [5,6], glucose [7,8], and phospholipid [9] metabolism, aberrant calcium homeostasis [10], and mitochondrial dysfunction [11]. These features of AD have received far less attention because of the lack of direct links to the amyloid cascade, and have engendered numerous competing hypotheses to explain the pathogenesis of AD.…”

mentioning

confidence: 99%

Is Alzheimer's Disease a Disorder of Mitochondria-Associated Membranes?

Schon

Area‐Gómez

2010

JAD

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Abstract. The subcellular localization of presenilin-1 (PS1) and presenilin-2 (PS2), two proteins that, when mutated, cause familial Alzheimer's disease (AD), is controversial. We have discovered that mitochondria-associated membranes (MAM) -a specialized subcompartment of the endoplasmic reticulum (ER) involved in lipid metabolism and calcium homeostasis that physically connects ER to mitochondria -is the predominant subcellular location for PS1 and PS2, and for γ-secretase activity. We hypothesize that presenilins play a role in maintaining MAM function, and that not only altered amyloid-β levels and hyperphosphorylated tau, but also many other features of AD (e.g., altered phospholipid and cholesterol metabolism, aberrant calcium homeostasis, and abnormal mitochondrial dynamics) result from compromised MAM function. The localization of presenilins and γ-secretase in MAM may help reconcile disparate ideas regarding the pathogenesis of AD, under a unifying hypothesis that could explain many features of both sporadic and familial AD, thereby taking AD research in a new and fruitful direction.Keywords: Alzheimer's disease, calcium, cholesterol, endoplasmic reticulum (ER), mitochondria, mitochondria-associated membranes (MAM), phospholipids ALZHEIMER'S DISEASEAlzheimer's disease (AD), the most common late onset neurodegenerative dementing disorder, is characterized by progressive neuronal loss, especially in the hippocampus and cortex [1]. The two main histopathological hallmarks of AD are the accumulation of extracellular neuritic plaques, containing amyloid-β (Aβ), and of neurofibrillary tangles, consisting mainly of hyperphosphorylated forms of the microtubule-associated protein tau [1]. Most AD patients are sporadic (SAD), but three genes have been associated with the familial form (FAD): amyloid-β protein precursor (AβPP), presenilin-1 (PS1), and presenilin-2 (PS2). Clinically, FAD is similar to SAD but has earlier onset. Presenilins are components of the γ-secretase complex (also containing APH1, nicastrin, and PEN2) that, together with β-secretase, processes AβPP to produce Aβ [1]. In the mainstream view, both SAD and FAD arise when AβPP is processed to Aβ, which accumulates in extracellular plaques. Aβ is toxic to cells and the resulting stress promotes tau hyperphosphorylation, leading to the tangles. The overall process has been called the "amyloid cascade" hypothesis [2,3]. This hypothesis reconciles findings from different approaches to the disease and has served as the basis for many key experiments in vivo and in vitro. However, certain questions that are central to understanding the pathogenesis of AD and the processing of Aβ remain unsolved.The first question concerns features of AD that are not obviously linked to plaque or tangle formation. While plaques and tangles are hallmarks of the disease, other apparently unrelated laboratory abnormali-

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Lipid Alterations in Lipid Rafts from Alzheimer's Disease Human Brain Cortex

Cited by 241 publications

References 69 publications

Lipid metabolism in Alzheimer’s disease

Lipid metabolism in Alzheimer’s disease

Severe Alterations in Lipid Composition of Frontal Cortex Lipid Rafts from Parkinson’s Disease and Incidental Parkinson’s Disease

Is Alzheimer's Disease a Disorder of Mitochondria-Associated Membranes?

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