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

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      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 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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        Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts

        Formation of senile plaques containing the β-amyloid peptide (Aβ) derived from the amyloid precursor protein (APP) is an invariant feature of Alzheimer's disease (AD). APP is cleaved either by β-secretase or by α-secretase to initiate amyloidogenic (release of Aβ) or nonamyloidogenic processing of APP, respectively. A key to understanding AD is to unravel how access of these enzymes to APP is regulated. Here, we demonstrate that lipid rafts are critically involved in regulating Aβ generation. Reducing cholesterol levels in N2a cells decreased Aβ production. APP and the β-site APP cleavage enzyme (BACE1) could be induced to copatch at the plasma membrane upon cross-linking with antibodies and to segregate away from nonraft markers. Antibody cross-linking dramatically increased production of Aβ in a cholesterol-dependent manner. Aβ generation was dependent on endocytosis and was reduced after expression of the dynamin mutant K44A and the Rab5 GTPase-activating protein, RN-tre. This inhibition could be overcome by antibody cross-linking. These observations suggest the existence of two APP pools. Although APP inside raft clusters seems to be cleaved by β-secretase, APP outside rafts undergoes cleavage by α-secretase. Thus, access of α- and β-secretase to APP, and therefore Aβ generation, may be determined by dynamic interactions of APP with lipid rafts.
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          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

            Author and article information

            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@

            Guest Editor: B. O. Popescu

            J Cell Mol Med
            J. Cell. Mol. Med
            Journal of Cellular and Molecular Medicine
            Blackwell Publishing Ltd (Oxford, UK )
            November 2007
            22 October 2007
            : 11
            : 6
            : 1227-1238

            Molecular medicine

            neurodegeneration, alzheimer's disease, apolipoprotein e


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