Cellular cholesterol homeostasis and Alzheimer's disease

Chang, Ta Yuan; Yamauchi, Yoshio; Hasan, Mazahir T.; Chang, Catherine C.Y.

doi:10.1194/jlr.r075630

Cited by 123 publications

(109 citation statements)

References 232 publications

(236 reference statements)

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“…It is characterized by intraneuronal neurofibrillary tangles (NFTs) containing highly phosphorylated tau and senile plaques composed of Aβ filaments, along with selective neuronal death in affected brain regions. Although the etiology of AD is unknown, it is believed that both environmental and genetic factors are involved among which disturbances in cholesterol metabolism have been implicated . Longitudinal studies revealed the positive correlation between higher blood concentration of total and low‐density lipoprotein cholesterol and faster global cognitive decline in late‐life .…”

Section: Introductionmentioning

confidence: 99%

The sterol regulatory element‐binding protein 2 is dysregulated by tau alterations in Alzheimer disease

et al. 2019

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Disturbed neuronal cholesterol homeostasis has been observed in Alzheimer disease (AD) and contributes to the pathogenesis of AD. As the master switch of cholesterol biosynthesis, the sterol regulatory element-binding protein 2 (SREBP-2) translocates to the nucleus after cleavage/activation, but its expression and activation have not been studied in AD which is the focus of the current study. We found both a significant decrease in the nuclear translocation of N-terminal SREBP-2 accompanied by a significant accumulation of C-terminal SREBP-2 in NFT-containing pyramidal neurons in AD. N-terminal-SREBP-2 is also found in dystrophic neurites around plaques in AD brain. Western blot confirmed a significantly reduced nuclear translocation of mature SREBP-2 (mSREBP-2) in AD brain. Interestingly, reduced nuclear mSREBP-2 was only found in animal models of tauopathies such as 3XTg AD mice and P301L Tau Tg mice but not in CRND8 APP transgenic mice, suggesting that tau alterations likely are involved in the changes of mSREBP-2 distribution and activation in AD. Altogether, our study demonstrated disturbed SREBP-2 signaling in AD and related models, and proved for the first time that tau alterations contribute to disturbed cholesterol homeostasis in AD likely through modulation of nuclear mSREBP-2 translocation.

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Section: Introductionmentioning

confidence: 99%

The sterol regulatory element‐binding protein 2 is dysregulated by tau alterations in Alzheimer disease

et al. 2019

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“…Abnormal cholesterol metabolism is an established feature of AD: levels of cholesterol are increased in MCI subjects and levels of 24-hydroxycholesterol and 27-hydroxycholesterol are elevated compared to controls both in AD and MCI subjects [24]. It appears that the rate of cholesterol production may be boosted by a free radical attack via a constitutive activation of HMGCoA-reductase, the rate-limiting step in sterol biosynthesis.…”

Section: Ad-associated Changes In Cholesterol Metabolismmentioning

confidence: 99%

Primary Prevention of Alzheimer’s Disease (AD)

Bergamini¹,

Cavallini²

2019

Geriatric Medicine and Gerontology

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Alzheimer dementia (AD) is a complex, aging-associated disease whose effects on the brain (an organ made up by nonreplaceable cells) are devastating. Disease is not curable, but progress in pathobiology shows that intervention on aging can make primary prevention of AD feasible. According to the amyloid-cascade hypothesis, mechanisms of AD include: an age-related alteration of free radical metabolism in membranes, leading to a higher yield in the toxic Aβ1-42 peptide and an overwhelming impact on the weaker repair mechanisms of the aging cells. The proposed intervention on aging with anti-AD effects includes a daily assumption of antioxidants (red wine polyphenols enriched with resveratrol), a reinforcement of membrane antioxidant defenses by the assumption of polyunsaturated fatty acids at the first meal after fasting, and an enhancement of cell repair function (at the proteasome and autophagy level by an intermittent feeding regimen and physical exercise plus the assumption of antilipolytic agents during time of fasting). The beneficial effects of diet and physical activity on the endogenous production of protective nerve growth factors are magnified by an enriched environment. Treatment has already been started on healthy individuals at a higher risk of AD in the city of Volterra.

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“…This review focuses on discussing the connection between sterol metabolism and atherosclerosis as well as cancers. For a detailed discussion between cholesterol metabolism and neurodegenerative diseases, a recent review by Chang et al ( 201 ) is available. Detailed reviews on the roles of sterols in immune responses are available elsewhere ( 20 , 202 ).…”

Section: Sterols and Human Diseasesmentioning

confidence: 99%

Sterol Metabolism and Transport in Atherosclerosis and Cancer

Yamauchi

Rogers

2018

Front. Endocrinol.

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Cholesterol is a vital lipid molecule for mammalian cells, regulating fluidity of biological membranes, and serving as an essential constituent of lipid rafts. Mammalian cells acquire cholesterol from extracellular lipoproteins and from de novo synthesis. Cholesterol biosynthesis generates various precursor sterols. Cholesterol undergoes metabolic conversion into oxygenated sterols (oxysterols), bile acids, and steroid hormones. Cholesterol intermediates and metabolites have diverse and important cellular functions. A network of molecular machineries including transcription factors, protein modifiers, sterol transporters/carriers, and sterol sensors regulate sterol homeostasis in mammalian cells and tissues. Dysfunction in metabolism and transport of cholesterol, sterol intermediates, and oxysterols occurs in various pathophysiological settings such as atherosclerosis, cancers, and neurodegenerative diseases. Here we review the cholesterol, intermediate sterol, and oxysterol regulatory mechanisms and intracellular transport machineries, and discuss the roles of sterols and sterol metabolism in human diseases.

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Cellular cholesterol homeostasis and Alzheimer's disease

Cited by 123 publications

References 232 publications

The sterol regulatory element‐binding protein 2 is dysregulated by tau alterations in Alzheimer disease

The sterol regulatory element‐binding protein 2 is dysregulated by tau alterations in Alzheimer disease

Primary Prevention of Alzheimer’s Disease (AD)

Sterol Metabolism and Transport in Atherosclerosis and Cancer

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