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      Connecting the brain cholesterol and renin-angiotensin systems: potential role of statins and RAS-modifying medications in dementia

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          Most cited references165

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          The role of apolipoprotein E in Alzheimer's disease.

          The epsilon4 allele of apolipoprotein E (APOE) is the major genetic risk factor for Alzheimer's disease (AD). Although there have been numerous studies attempting to elucidate the underlying mechanism for this increased risk, how apoE4 influences AD onset and progression has yet to be proven. However, prevailing evidence suggests that the differential effects of apoE isoforms on Abeta aggregation and clearance play the major role in AD pathogenesis. Other potential mechanisms, such as the differential modulation of neurotoxicity and tau phosphorylation by apoE isoforms as well as its role in synaptic plasticity and neuroinflammation, have not been ruled out. Inconsistent results among studies have made it difficult to define whether the APOE epsilon4 allele represents a gain of toxic function, a loss of neuroprotective function, or both. Therapeutic strategies based on apoE propose to reduce the toxic effects of apoE4 or to restore the physiological, protective functions of apoE.
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            Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors.

            Increasing evidence suggests that cholesterol plays a role in the pathophysiology of Alzheimer disease (AD). For instance, an elevated serum cholesterol level has been shown to be a risk factor for AD. To determine whether patients taking 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), which are a group of medicines that inhibit the synthesis of cholesterol, have a lower prevalence of probable AD. The experiment uses a cross-sectional analysis comparing the prevalence of probable AD in 3 groups of patients from hospital records: the entire population, patients receiving 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (hereafter referred to as the statins), and patients receiving medications used to treat hypertension or cardiovascular disease. The subjects studied were those included in the computer databases of 3 different hospitals for the years October 1, 1996, through August 31, 1998. Diagnosis of probable AD. We find that the prevalence of probable AD in the cohort taking statins during the study interval is 60% to 73% (P < .001) lower than the total patient population or compared with patients taking other medications typically used in the treatment of hypertension or cardiovascular disease. There is a lower prevalence of diagnosed probable AD in patients taking 2 different 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors-lovastatin and pravastatin. While one cannot infer causative mechanisms based on these data, this study reveals an interesting association in the data, which warrants further study. Arch Neurol. 2000;57:1439-1443
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              Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model.

              Recent data suggest that cholesterol metabolism is linked to susceptibility to Alzheimer's disease (AD). However, no direct evidence has been reported linking cholesterol metabolism and the pathogenesis of AD. To test the hypothesis that amyloid beta-peptide (Abeta) deposition can be modulated by diet-induced hypercholesterolemia, we used a transgenic-mouse model for AD amyloidosis and examined the effects of a high-fat/high-cholesterol diet on central nervous system (CNS) Abeta accumulation. Our data showed that diet-induced hypercholesterolemia resulted in significantly increased levels of formic acid-extractable Abeta peptides in the CNS. Furthermore, the levels of total Abeta were strongly correlated with the levels of both plasma and CNS total cholesterol. Biochemical analysis revealed that, compared with control, the hypercholesterolemic mice had significantly decreased levels of sAPPalpha and increased levels of C-terminal fragments (beta-CTFs), suggesting alterations in amyloid precursor protein processing in response to hypercholesterolemia. Neuropathological analysis indicated that the hypercholesterolemic diet significantly increased beta-amyloid load by increasing both deposit number and size. These data demonstrate that high dietary cholesterol increases Abeta accumulation and accelerates the AD-related pathology observed in this animal model. Thus, we propose that diet can be used to modulate the risk of developing AD. Copyright 2000 Academic Press.
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                Author and article information

                Journal
                Journal of Internal Medicine
                J Intern Med
                Wiley
                09546820
                December 2018
                December 2018
                October 28 2018
                : 284
                : 6
                : 620-642
                Affiliations
                [1 ]Division of Neurogeriatrics; Department of Neurobiology, Care Sciences and Society; Karolinska Institutet; Stockholm Sweden
                [2 ]Department of Neurology; University Medical Centre; Ljubljana Slovenia
                [3 ]University of Ljubljana; Ljubljana Slovenia
                [4 ]Division of Clinical Geriatrics; Department of Neurobiology, Care Sciences and Society; Karolinska Institutet; Stockholm Sweden
                [5 ]Center for Alzheimer Research; Division of Neurogeriatrics; Department of Neurobiology, Care Sciences and Society; Karolinska Institutet; Stockholm Sweden
                [6 ]Department of Neurosciences; Biodonostia Health Research Institute; San Sebastian Spain
                [7 ]Center for Networked Biomedical Research in Neurodegenerative Diseases, CIBERNED; Health Institute Carlos III; Ministry of Economy and Competitiveness; Madrid Spain
                [8 ]Department of Geriatric Medicine; Karolinska University Hospital; Stockholm Sweden
                [9 ]Theme Neuro; Diseases of the Nervous System patient flow; Karolinska University Hospital; Huddinge Sweden
                [10 ]Department of Internal Medicine; Neurology Section; Södersjukhuset; Stockholm Sweden
                Article
                10.1111/joim.12838
                30264910
                c2f8ff38-e9eb-4561-9765-99d5b14c0d83
                © 2018

                http://doi.wiley.com/10.1002/tdm_license_1.1

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