Role of LDL Cholesterol and Endolysosomes in Amyloidogenesis and Alzheimer’s Disease

Chen, Xuesong; Liang, Hui; Geiger, Jonathan D.

doi:10.4172/2155-9562.1000236

Cited by 20 publications

(9 citation statements)

References 131 publications

(131 reference statements)

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“…However, we found that EPA or DHA at the same dose as ALA markedly decreased brain content of LDL, SFAs and AA. The accumulation of LDL and SFAs are highly related to the development of stroke, atherosclerosis, thrombosis or even neurodegenerative diseases [ 25 , 26 ]. Since EPA or DHA substantially lowered brain LDL and SFAs levels under aging condition, the intake of these two PUFAs may reduce the occurrence of the above disorders.…”

Section: Discussionmentioning

confidence: 99%

EPA or DHA enhanced oxidative stress and aging protein expression in brain of d-galactose treated mice

Hsu¹,

Yin²

2016

BioMed

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Background:Effects of eicosapentaenoic acid (EPA, 20:5) and docosahexaenoic acid (DHA, 22:6) upon fatty acid composition, oxidative and inflammatory factors and aging proteins in brain of d-galactose (DG) treated aging mice were examined.Methods:Each fatty acid at 7 mg/kg BW/week was supplied for 8 weeks. Brain aging was induced by DG treatment (100 mg/kg body weight) via daily subcutaneous injection for 8 weeks.Results:DG, EPA and DHA treatments changed brain fatty acid composition. DG down-regulated brain Bcl-2 expression and up-regulated Bax expression. Compared with DG groups, EPA and DHA further enhanced Bax expression. DG decreased glutathione content, increased reactive oxygen species (ROS) and oxidized glutathione (GSSG) production, the intake of EPA or DHA caused greater ROS and GSSG formation. DG treatments up-regulated the protein expression of p47phox and gp91phox, and the intake of EPA or DHA led to greater p47phox and gp91phox expression. DG increased brain prostaglandin E2 (PGE2) levels, and cyclooxygenase (COX)-2 expression and activity, the intake of EPA or DHA reduced brain COX-2 activity and PGE2 formation. DG enhanced brain p53, p16 and p21 expression. EPA and DHA intake led to greater p21 expression, and EPA only caused greater p53 and p16 expression. Conclusion: These findings suggest that these two PUFAs have toxic effects toward aging brain.

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Section: Discussionmentioning

confidence: 99%

EPA or DHA enhanced oxidative stress and aging protein expression in brain of d-galactose treated mice

Hsu¹,

Yin²

2016

BioMed

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“…This is to say, the increased prevalence and risk for AD among women can be explained in part by the abrupt decrease in estrogen production that accompanies the post-menopausal state. Not only does the lack of estrogen decrease concentrations of anti-inflammatory LC-PUFAs and HDL-C in the body, but it also increases TG levels, augmenting secretion of VLDL (very-low density lipoprotein), a lipid carrier known to induce neuroinflammation (Burgess et al, 2006;Chen et al, 2014;Nägga et al, 2018). Additionally, genetic factors, such as ApoE status, and social determinants, such as education, mental illness, and diet, interact with the post-menopausal state to amplify these detrimental effects, increasing risk of AD.…”

Section: Lipids and Sexmentioning

confidence: 99%

Involvement of Lipids in Alzheimer’s Disease Pathology and Potential Therapies

2020

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Lipids constitute the bulk of the dry mass of the brain and have been associated with healthy function as well as the most common pathological conditions of the brain. Demographic factors, genetics, and lifestyles are the major factors that influence lipid metabolism and are also the key components of lipid disruption in Alzheimer's disease (AD). Additionally, the most common genetic risk factor of AD, APOE 4 genotype, is involved in lipid transport and metabolism. We propose that lipids are at the center of Alzheimer's disease pathology based on their involvement in the blood-brain barrier function, amyloid precursor protein (APP) processing, myelination, membrane remodeling, receptor signaling, inflammation, oxidation, and energy balance. Under healthy conditions, lipid homeostasis bestows a balanced cellular environment that enables the proper functioning of brain cells. However, under pathological conditions, dyshomeostasis of brain lipid composition can result in disturbed BBB, abnormal processing of APP, dysfunction in endocytosis/exocytosis/autophagocytosis, altered myelination, disturbed signaling, unbalanced energy metabolism, and enhanced inflammation. These lipid disturbances may contribute to abnormalities in brain function that are the hallmark of AD. The wide variance of lipid disturbances associated with brain function suggest that AD pathology may present as a complex interaction between several metabolic pathways that are augmented by risk factors such as age, genetics, and lifestyles. Herewith, we examine factors that influence brain lipid composition, review the association of lipids with all known facets of AD pathology, and offer pointers for potential therapies that target lipid pathways.

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“…Consistent with this idea, APOE ε4, but not APOE ε3, in a thiorphan-treated APP mouse model of AD, expands lysosomal compartments, increases Aβ co-localization with lysosomes, and causes learning and memory impairment (Belinson et al, 2008). Cholesterol, the principal lipid carried into neurons by ApoE, and a suspected AD risk factor (Chen et al, 2014a; Chen et al, 2014b), also induces neuronal rab5 activation and endocytic upregulation when administered to animals through a high-fat diet (Braccini et al, 2015). Evidence suggests that membrane cholesterol may also influence v-ATPase function more directly.…”

Section: V-atpase –Related Lysosomal Acidification Failure In Diseasementioning

confidence: 99%

Disorders of lysosomal acidification—The emerging role of v-ATPase in aging and neurodegenerative disease

Colacurcio

Nixon

2016

Ageing Research Reviews

401

329

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Autophagy and endocytosis deliver unneeded cellular materials to lysosomes for degradation. Beyond processing cellular waste, lysosomes release metabolites and ions that serve signaling and nutrient sensing roles, linking the functions of the lysosome to various pathways for intracellular metabolism and nutrient homeostasis. Each of these lysosomal behaviors is influenced by the intraluminal pH of the lysosome, which is maintained in the low acidic range by a proton pump, the vacuolar ATPase (v-ATPase). New reports implicate altered v-ATPase activity and lysosomal pH dysregulation in cellular aging, longevity, and adult-onset neurodegenerative diseases, including forms of Parkinson Disease and Alzheimer Disease. Genetic defects of subunits composing the v-ATPase or v-ATPase-related proteins occur in an increasingly recognized group of familial neurodegenerative diseases. Here, we review the expanding roles of the v-ATPase complex as a platform regulating lysosomal proteolysis and cellular homeostasis. We discuss the unique vulnerability of neurons to persistent low level lysosomal dysfunction and review recent clinical and experimental studies that link dysfunction of the v-ATPase complex to neurodegenerative diseases across the age spectrum.

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Role of LDL Cholesterol and Endolysosomes in Amyloidogenesis and Alzheimer’s Disease

Cited by 20 publications

References 131 publications

EPA or DHA enhanced oxidative stress and aging protein expression in brain of d-galactose treated mice

EPA or DHA enhanced oxidative stress and aging protein expression in brain of d-galactose treated mice

Involvement of Lipids in Alzheimer’s Disease Pathology and Potential Therapies

Disorders of lysosomal acidification—The emerging role of v-ATPase in aging and neurodegenerative disease

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