Fatty Acid Composition of Frontal, Temporal and Parietal Neocortex in the Normal Human Brain and in Alzheimer’s Disease

Fraser, T.; Tayler, Hannah; Love, Seth

doi:10.1007/s11064-009-0087-5

Cited by 167 publications

(107 citation statements)

References 36 publications

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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.…”

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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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confidence: 99%

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

Schon

Area‐Gómez

2010

JAD

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“…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] .…”

Section: Role Of Fatty-acid Metabolism In Ad Pathogenesismentioning

confidence: 89%

“…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: 79%

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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“…Both C22:6n-3 and C20:4n-6 remained unchanged in HF, as well as the total n-3 and total n-6 PUFAs. C22:6n-3 and C20:4n-6 are the main fatty acids in the medial basal hypothalamus of cows (67), and the main fatty acids in major neural systems in humans (68,69). We hypothesise increased C20:5n-3 and C20:3n-6, followed by unchanged C22:6n-3 and C20:4n-6 in HF hypothalamus is the result of a protective mechanism in which peripheral tissues supply these fatty acids, as evidenced by their reduced levels in peripheral tissues.…”

Section: We Did Not Find Any Differences In Hypothalamic Levels Of Irmentioning

confidence: 99%