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      Apolipoprotein E and Alzheimer's disease: molecular mechanisms and therapeutic opportunities

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          Abstract

          Multiple genetic and environmental factors are likely to contribute to the development of Alzheimer's disease (AD). The most important known risk factor for AD is presence of the E4 isoform of apolipoprotein E (apoE). Epidemiological studies demonstrated that apoE4 carriers have a higher risk and develop the disease and an early onset. Moreover, apoE4 is the only molecule that has been associated with all the biochemical disturbances characteristic of the disease: amyloid-beta (Aβ) deposition, tangle formation, oxidative stress, lipid homeostasis deregulation, synaptic plasticity loss and cholinergic dysfunction. This large body of evidence suggest that apoE is a key player in the pathogenesis of AD. This short review examines the current facts and hypotheses of the association between apoE4 and AD, as well as the therapeutic possibilities that apoE might offer for the treatment of this disease.

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          Alzheimer's disease.

          Kaj Blennow, Mony J. de Leon, Henrik Zetterberg (2006)
          Alzheimer's disease is the most common cause of dementia. Research advances have enabled detailed understanding of the molecular pathogenesis of the hallmarks of the disease--ie, plaques, composed of amyloid beta (Abeta), and tangles, composed of hyperphosphorylated tau. However, as our knowledge increases so does our appreciation for the pathogenic complexity of the disorder. Familial Alzheimer's disease is a very rare autosomal dominant disease with early onset, caused by mutations in the amyloid precursor protein and presenilin genes, both linked to Abeta metabolism. By contrast with familial disease, sporadic Alzheimer's disease is very common with more than 15 million people affected worldwide. The cause of the sporadic form of the disease is unknown, probably because the disease is heterogeneous, caused by ageing in concert with a complex interaction of both genetic and environmental risk factors. This seminar reviews the key aspects of the disease, including epidemiology, genetics, pathogenesis, diagnosis, and treatment, as well as recent developments and controversies.
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            Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors.

            B Wolozin, W Kellman, P Ruosseau … (2000)
            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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              Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the alpha -secretase ADAM 10.

              G Gimpl, W März, E Kojro … (2001)
              Biochemical, epidemiological, and genetic findings demonstrate a link between cholesterol levels, processing of the amyloid precursor protein (APP), and Alzheimer's disease. In the present report, we identify the alpha-secretase ADAM 10 (a disintegrin and metalloprotease) as a major target of the cholesterol effects on APP metabolism. Treatment of various peripheral and neural cell lines with either the cholesterol-extracting agent methyl-beta-cyclodextrin or the hydroxymethyl glutaryl-CoA reductase inhibitor lovastatin resulted in a drastic increase of secreted alpha-secretase cleaved soluble APP. This strong stimulatory effect was in the range obtained with phorbol esters and was further increased in cells overexpressing ADAM 10. In cells overexpressing APP, the increase of alpha-secretase activity resulted in a decreased secretion of Abeta peptides. Several mechanisms were elucidated as being the basis of enhanced alpha-secretase activity: increased membrane fluidity and impaired internalization of APP were responsible for the effect observed with methyl-beta-cyclodextrin; treatment with lovastatin resulted in higher expression of the alpha-secretase ADAM 10. Our results demonstrate that cholesterol reduction promotes the nonamyloidogenic alpha-secretase pathway and the formation of neuroprotective alpha-secretase cleaved soluble APP by several mechanisms and suggest approaches to prevention of or therapy for Alzheimer's disease.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Cell Mol Med
                Journal ID (iso-abbrev): J. Cell. Mol. Med
                Journal ID (publisher-id): jcmm
                Title: Journal of Cellular and Molecular Medicine
                Publisher: Blackwell Publishing Ltd (Oxford, UK )
                ISSN (Print): 1582-1838
                ISSN (Electronic): 1582-4934
                Publication date (Print): November 2007
                Publication date (Electronic): 22 October 2007
                Volume: 11
                Issue: 6
                Pages: 1227-1238
                Affiliations
                Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, KI-Alzheimer's Disease Research Center, NOVUM, Stockholm, Sweden
                Author notes
                *Correspondence to: Angel CEDAZO-MÍNGUEZ, Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, KI-Alzheimer's Disease Research Center, NOVUM, 5th floor, SE-14186 Stockholm, Sweden. Tel.: +46 8-58 5-83 75 1 Fax: +46 8-58 5-83 88 0 E-mail: Angel.Cedazo-Minguez@ 123456ki.se

                Guest Editor: B. O. Popescu

                Article
                DOI: 10.1111/j.1582-4934.2007.00130.x
                PMC ID: 4401287
                PubMed ID: 18205697
                SO-VID: f3660ace-16a6-4ecb-8bb8-31f7f08f1d89
                History
                Date received : 22 September 2007
                Date accepted : 03 October 2007
                Categories
                Subject: Reviews

                ScienceOpen disciplines: Molecular medicine
                Keywords: apolipoprotein e,alzheimer's disease,neurodegeneration
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: apolipoprotein e, alzheimer's disease, neurodegeneration

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