Evidence for benefit of statins to modify cognitive decline and risk in Alzheimer’s disease

Geifman, Nophar; Brinton, Roberta Dı́az; Kennedy, Richard E.; Schneider, Lon S.; Butte, Atul J.

doi:10.1186/s13195-017-0237-y

Cited by 159 publications

(147 citation statements)

References 65 publications

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“…Studies have indicated a connection between the ApoE4 allele on the apolipoprotein gene with hypercholesterolemia and increased risk of development of Alzheimer's disease [16]. Greater than 50% of subjects participating in clinical trials of Alzheimer's disease are positive for ApoE4 [17]. Similarly, two meta-analyses have reported a correlation between statin therapy and a reduced risk in the development of Parkinson's disease [18,19].…”

Section: Introductionmentioning

confidence: 99%

Rosuvastatin alleviates high-salt and cholesterol diet-induced cognitive impairment in rats via Nrf2–ARE pathway

et al. 2018

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Objective: The objectives of our study were to investigate the possible effect of rosuvastatin in ameliorating high salt and cholesterol diet (HSCD)-induced cognitive impairment and to also investigate its possible action via the Nrf2-ARE pathway. Methods: In silico studies were performed to check the theoretical binding of rosuvastatin to the Nrf2 target. HSCD was used to induce cognitive impairment in rats and neurobehavioral studies were performed to evaluate the efficacy of rosuvastatin in enhancing cognition. Biochemical analyses were used to estimate changes in oxidative markers. Western blot and immunohistochemical analyses were done to check Nrf2 translocation. TUNEL and caspase 3 tests were performed to evaluate reversal of apoptosis by rosuvastatin. Results: Rosuvastatin showed good theoretical affinity to Nrf2, significantly reversed changes in oxidative biomarkers which were induced by HSCD, and also improved the performance of rats in the neurobehavioral test. A rise in nuclear translocation of Nrf2 was revealed through immunohistochemical analysis and western blot. TUNEL staining and caspase 3 activity showed attenuation of apoptosis. Discussion: We have investigated a novel mechanism of action for rosuvastatin (via the Nrf2-ARE pathway) and demonstrated that it has the potential to be used in the treatment of cognitive impairment. KEYWORDSCognitive impairment; rosuvastatin; high-salt and cholesterol diet; oxidative stress; Nrf2; nuclear factor (erythroid-derived 2)-like 2

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Section: Introductionmentioning

confidence: 99%

Rosuvastatin alleviates high-salt and cholesterol diet-induced cognitive impairment in rats via Nrf2–ARE pathway

et al. 2018

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“…Furthermore, statins belong to a class of lipidlowering drugs widely used in the treatment of hyperlipidemia. Based on neurodegenerative disease research, different statins may have a beneficial effect in the treatment of dementia [5], PD [6], and Alzheimer's disease [7].…”

Section: Introductionmentioning

confidence: 99%

Simvastatin Protects Dopaminergic Neurons Against MPP+-Induced Oxidative Stress and Regulates the Endogenous Anti-Oxidant System Through ERK

Yan

Qiao

et al. 2018

Cell Physiol Biochem

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Background/Aims: Many clinical studies have demonstrated that statins, especially simvastatin, can decrease the incidence of Parkinson’s disease (PD). However, the specific underlying mechanism remains unclear. This study aimed to investigate how simvastatin affects experimental parkinsonian models via the regulation of extracellular signal-regulated kinase 1/2 (ERK1/2)-mediated activation of the anti-oxidant system. Methods: l-Methyl-4-phenylpyridine ion (MPP⁺)-treated SH-SY5Y cells and substantia nigra neurons were used to investigate the neuroprotective effect of simvastatin. After incubation with MPP⁺ and/or simvastatin for 24 h, the MTT assay was used to assess cell viability. Reactive oxygen species (ROS) levels were measured using 2′,7′-dichlorofluorescin diacetate, while cellular superoxide dismutase (SOD) levels were determined based on the blue formazan produced by the reduction of nitroblue tetrazolium. The level of cellular grade micro-reduced glutathione (GSH) was measured with 5,5’-dithiobis-(2-nitrobenzoic acid). Meanwhile, the malondialdehyde content released from SH-SY5Y cells and substantia nigra neuronal cells exposed to different culture media was calculated based on the condensation reaction involving thiobarbituric acid. The mRNA levels of genes encoding nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase 1 (HO-1), and NAD(P)H dehydrogenase (quinone) 1 (NQO-1) were determined by a quantitative polymerase chain reaction assay, while the ERK, Nrf2, HO-1, NOX2, and NQO-1 protein levels were analyzed by western blot. Additionally, ERK small interfering RNA (siRNA) was used to investigate the mechanisms underlying MPP⁺-induced oxidative stress and the regulation of the endogenous anti-oxidant system. Results: Simvastatin (1.5 μM) enhanced the viability of SH-SY5Y cells and primary neurons treated with MPP⁺, and significantly alleviated the oxidative stress induced by MPP⁺ in SH-SY5Y cells by regulating the production of SOD, analytical grade micro-reduced GSH, and ROS, which may be associated with the activation of the Nrf2 anti-oxidant system. An analysis involving ERK1/2 siRNA revealed that simvastatin can inhibit NOX2 expression via the activation of ERK1/2 in the MPP⁺-treated PD cell model. Conclusion: Our results provide strong evidence that ERK1/2-mediated modulation of the anti-oxidant system after simvastatin treatment may partially explain the anti-oxidant activity in experimental parkinsonian models. These findings contribute to a better understanding of the critical roles of simvastatin via the ERK1/2-mediated modulation of the anti-oxidant system, which may be relevant for treating PD.

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“…Proposed explanations for the heterogeneity of any medication effects have included variation in the type of statin [52, 53, 55], genetic background [52], age of intervention [51], degree of cognitive impairment [10], and race/ethnicity and gender [53]. Our findings from a large, population-based sample support a unifying hypothesis – namely, that chronic statin use in mid- to late-life does not appear to impact neuroimaging biomarkers of typical AD but may have the capacity to influence brain structure and function and the resultant risk of dementia through modifying cerebrovascular health.…”

Section: Discussionmentioning

confidence: 99%

Statins and Brain Health: Alzheimer’s Disease and Cerebrovascular Disease Biomarkers in Older Adults

Ramanan

Przybelski

Graff‐Radford

et al. 2018

JAD

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Background: Statins have been proposed to reduce the risk of Alzheimer’s disease (AD). Objective: Assess whether long-term statin use was associated with neuroimaging biomarkers of aging and dementia. Methods: We analyzed neuroimaging biomarkers in 1160 individuals aged 65+ from the Mayo Clinic Study of Aging, a population-based prospective longitudinal study of cognitive aging. Results: Statin-treated (5+ years of therapy) individuals had greater burden of mid- and late-life cardiovascular disease (p<0.001) than statin-untreated (≤3 months) individuals. Lower fractional anisotropy in the genu of the corpus callosum, an early marker of cerebrovascular disease, was associated with long-term statin exposure (p<0.035). No significant associations were identified between long-term statin exposure and cerebral amyloid or tau burden, AD pattern neurodegeneration, or white matter hyperintensity burden. Conclusion: Long-term statin therapy was not associated with differences in AD biomarkers. Individuals with long-term statin exposure had worse white matter integrity in the genu of the corpus callosum, consistent with the coexistence of higher cerebrovascular risk factor burden in this group.

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Evidence for benefit of statins to modify cognitive decline and risk in Alzheimer’s disease

Cited by 159 publications

References 65 publications

Rosuvastatin alleviates high-salt and cholesterol diet-induced cognitive impairment in rats via Nrf2–ARE pathway

Rosuvastatin alleviates high-salt and cholesterol diet-induced cognitive impairment in rats via Nrf2–ARE pathway

Simvastatin Protects Dopaminergic Neurons Against MPP+-Induced Oxidative Stress and Regulates the Endogenous Anti-Oxidant System Through ERK

Statins and Brain Health: Alzheimer’s Disease and Cerebrovascular Disease Biomarkers in Older Adults

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