Simvastatin improves cerebrovascular function and counters soluble amyloid-beta, inflammation and oxidative stress in aged APP mice

Tong, Xin‐Kang; Nicolakakis, Nektaria; Fernandes, Priscilla; Ongali, Brice; Brouillette, Jonathan; Quirion, Rémi; Hamel, Édith

doi:10.1016/j.nbd.2009.06.003

Cited by 108 publications

(109 citation statements)

References 56 publications

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“…Similarly, SR-BI activation could possibly have a beneficial effect in AD pathology. SR-BI expression has been shown to be induced by statins (39,40), and simvastatin treatment of J20 mice has shown a positive effect on cerebrovascular function (34). These data combined with ours suggest SR-BI as a potential mediator of the beneficial effect of statins in cerebrovascular function.…”

Section: Discussionsupporting

confidence: 71%

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Scavenger receptor class B type I (SR-BI) regulates perivascular macrophages and modifies amyloid pathology in an Alzheimer mouse model

Thanopoulou

Fragkouli

Stylianopoulou

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

124

114

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Scavenger receptor class B type I (SR-BI) is a high-density lipoprotein receptor that regulates cholesterol efflux from the peripheral tissues to the liver. SR-BI has been identified on astrocytes and vascular smooth muscle cells in Alzheimer's disease brain and has been shown to mediate adhesion of microglia to fibrillar amyloid-β (Aβ). Here we report that SR-BI mediates perivascular macrophage response and regulates Aβ-related pathology and cerebral amyloid angiopathy in an Alzheimer's mouse model. Reduction or deletion of SR-BI gene in heterozygous or homozygous deficient mice (SR-BI +/− , −/− ) resulted in a significant increase in perivascular macrophages in the brain. SR-BI deletion had no effect on apolipoprotein E or apolipoprotein AI levels in the mouse brain. Our analysis revealed increased levels of SR-BI expression in the brains of human amyloid precursor protein (Swedish, Indiana) transgenic mice (J20 line). To evaluate the role of SR-BI in Alzheimer's disease pathogenesis, we inactivated one SR-BI allele in J20 transgenic mice. SR-BI reduction in J20/SR-BI +/− mice enhanced fibrillar amyloid deposition and cerebral amyloid angiopathy and also exacerbated learning and memory deficits compared with J20 littermates. Immunohistochemical analysis revealed localization of SR-BI on perivascular macrophages in tight association with Aβ deposits. Our data suggest that SR-BI reduction impairs the response of perivascular macrophages to Aβ and enhances the Aβ-related phenotype and cerebral amyloid angiopathy in J20 mice. These results reveal that SR-BI, a scavenger receptor primarily involved in high-density lipoprotein cholesterol transport, plays an essential role in Alzheimer's disease and cerebral amyloid angiopathy.high-density lipoprotein receptor | dementia

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Section: Discussionsupporting

confidence: 71%

“…J20 mice have been shown to have increased production of superoxide (O 2 .− ) and elevated levels of superoxide dismutase-2 (SOD2) (34). Analysis of SOD2 expression in SR-BI +/+ and +/− mice as well as in J20/SR-BI +/− and J20 showed no changes, implying that SR-BI does not affect oxidative stress in the brain.…”

Section: Discussionmentioning

confidence: 99%

Scavenger receptor class B type I (SR-BI) regulates perivascular macrophages and modifies amyloid pathology in an Alzheimer mouse model

Thanopoulou

Fragkouli

Stylianopoulou

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

124

114

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“…The statin-decreased serum cholesterol was accompanied with lowed brain A levels in guinea pigs (Fassbender et al, 2001), transgenic (Tong et al, 2009) can not pass through the BBB could be more secure (Fonseca et al, 2010). Based on our data, fluvastatin could be one of more secure statins.…”

Section: Discussionmentioning

confidence: 55%

Reduction of A by fluvastatin associates with altered levels of APP and of BACE1 and ADAM10 mRNA, independent of brain total cholesterol in rats

Shi¹

2011

Afr. J. Pharm. Pharmacol.

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The aim of the present study was to determine the effects of fluvastatin, a relatively hydrophilic 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) inhibitor, on endogenous amyloid beta (A ) production and if such effects would be associated with changes in brain total cholesterol in rats. Wistar male rats were treated with fluvastatin at a dose of 20 mg/kg/day or vehicle (controls) by oral gavage for 28 days. We examined serum and brain cholesterol levels by CHOD-PAP method, brain A levels by radioimmunoassay, mRNA levels of HMGR and cholesterol 24S-hydroxylase (CYP46) involving in cholesterol balance, -secretase (BACE1) and -secretase (ADAM10) involving in amyloid beta precursor protein (A PP) processing by RT-PCR and protein levels of A PP by immunohistochemistry. Serum total cholesterol and brain A levels were significantly reduced in fluvastatin-treated rats. There was no change in total cholesterol levels, HMGR and CYP46 mRNA levels in the brain of fluvastatintreated rats. Fluvastatin reduced A PP protein levels and up-regulated ADAM10 but down-regulated BACE1 mRNA expression in rat brain under used condition. These results suggest that reduction of brain A levels by fluvastatin is associated with changes in level of A PP and A PP cleavage-related enzyme mRNA, and is independent of brain total cholesterol. It may contribute to one of neuroprotective effects of fluvastatin and reveal that administration of fluvastatin could be beneficial in the preventation of AD.

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“…More recently, this cholesterolinduced memory impairment has been correlated with a loss of dendritic integrity, cholinergic dysfunction, inflammation (43), enhanced cortical Ab and phosphorylated tau (44), all indications which resemble an AD-like pathology. In line with such observations, cholesterol-lowering drugs (i.e., statins) were found to reduce cerebral Ab (21,45,46), phosphorylated tau (46), inflammation (45), and memory deficits (46,47) in a variety of animal models. Whether statins act in the brain simply by lowering cholesterol biosynthesis or by a different mechanism, however, still remains an open question.…”

Section: Animal Studiesmentioning

confidence: 64%

Cholesterol and Alzheimer's disease: A still poorly understood correlation

et al. 2012

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SummaryA large amount of evidence suggests a pathogenic link between cholesterol homeostasis dysregulation and Alzheimer's disease (AD). In cell culture systems, the production of amyloidb (Ab) is modulated by cholesterol, and studies on animal models have consistently demonstrated that hypercholesterolemia is associated with an increased deposition of cerebral Ab peptides. Consequently, a number of epidemiological studies have examined the effects of cholesterol-lowering drugs (i.e., statins) in the prevention and the treatment of AD. However, while retrospective studies suggested a potential benefit of statin therapy, clinical trials produced inconsistent results. Here, we summarize the main findings from in vitro and in vivo research where the correlation between cholesterol and the neurodegenerative disorder was investigated. Recognition of this correlation could be an important step forward for our understanding of AD pathogenesis and, possibly, for the development of new therapeutic strategies.2012 IUBMB IUBMB Life, 64(12): 931-935, 2012

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Simvastatin improves cerebrovascular function and counters soluble amyloid-beta, inflammation and oxidative stress in aged APP mice

Cited by 108 publications

References 56 publications

Scavenger receptor class B type I (SR-BI) regulates perivascular macrophages and modifies amyloid pathology in an Alzheimer mouse model

Scavenger receptor class B type I (SR-BI) regulates perivascular macrophages and modifies amyloid pathology in an Alzheimer mouse model

Reduction of A by fluvastatin associates with altered levels of APP and of BACE1 and ADAM10 mRNA, independent of brain total cholesterol in rats

Cholesterol and Alzheimer's disease: A still poorly understood correlation

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