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

Cedazo-Mı́nguez, Ángel

doi:10.1111/j.1582-4934.2007.00130.x

Cited by 129 publications

(99 citation statements)

References 102 publications

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“…The lack of information of the effect of ApoE4 in controls prevents us to discriminate if the NCAM reduction is due to AD in ApoE4 carriers or just to the effect of the E4 isoform in general. It is known that ApoE4 carriers (with and without neurodegenerative disorders) have less synaptic plasticity and regeneration processes than E3 carriers [67]. On the other hand, the enhanced synaptic regenerative processes in non-carriers of the ApoE4 allele could lead to an enhanced NCAM synthesis/expression and therefore, could be masking NCAM decreases associated to AD.…”

Section: Discussionmentioning

confidence: 99%

Altered NCAM Expression Associated with the Cholinergic System in Alzheimer's Disease

Aisa

Gil-Bea

Solas

et al. 2010

JAD

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Abstract. Neurotransmitter system dysfunction and synapse loss have been recognized as hallmarks of Alzheimer's disease (AD). Our hypothesis is that specific neurochemical populations of neurons might be more vulnerable to degeneration in AD due to particular deficits in synaptic plasticity. We have studied, in postmortem brain tissue, the relationship between levels of synaptic markers (NCAM and BDNF), neurochemical measurements (cholinacetyltransferase activity, serotonin, dopamine, GABA, and glutamate levels), and clinical data (cognitive status measured as MMSE score). NCAM levels in frontal and temporal cortex from AD patients were significantly lower than control patients. Interestingly, these reductions in NCAM levels were associated to an ApoE4 genotype. Levels of BDNF were also significantly reduced in both frontal and temporal regions in AD patients. The ratio between plasticity markers and neurochemical measurements was used to study which of the neurochemical populations was particularly associated to plasticity changes. In both the frontal and temporal cortex, there was a significant reduction in the ChAT/NCAM ratio in AD samples compared to controls. None of the ratios to BDNF were different between control and AD samples. Furthermore, Pearson's product moment showed a significant positive correlation between MMSE score and the ChAT/NCAM ratio in frontal cortex (n = 19; r = 0.526*; p = 0.037) as well as in temporal cortex (n = 19; r = 0.601*; p = 0.018) in AD patients. Altogether, these data suggest a potential involvement of NCAM expressing neurons in the cognitive deficits in AD.

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Section: Discussionmentioning

confidence: 99%

Altered NCAM Expression Associated with the Cholinergic System in Alzheimer's Disease

Aisa

Gil-Bea

Solas

et al. 2010

JAD

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“…The genetic polymorphism of apolipoprotein E (apoE) has been reported by several studies to be involved in lipid metabolism abnormalities and in several metabolic diseases, such as Alzheimer disease and cataracts, in the general population. 4 ApoE is a plasma protein that serves as a ligand for low-density lipoprotein (LDL) receptors and is synthesized in various organs, including the liver, brain, spleen and kidney. This protein is present at high concentrations in interstitial fluid, where it appears to participate in the cholesterol distribution among cells by transferring excess cholesterol to those cells that require cholesterol.…”

Section: Introductionmentioning

confidence: 99%

Association of apolipoprotein E gene polymorphism with end-stage renal disease and hyperlipidemia in patients on long-term hemodialysis

et al. 2014

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“…Very recently, it was proposed that the earliest defect in NPC disease is accumulation of sphingosine ( 97 ). Using the class II amphiphile U18666A to induce ( 120,121 )]. In addition, recent genome wide association studies have provided compelling evidence that genetic variations in APOJ are associated with the risk of developing AD (122)(123)(124).…”

Section: Niemann-pick Diseasementioning

confidence: 99%

Genetic connections between neurological disorders and cholesterol metabolism

Björkhem

Leoni²,

Meaney³

2010

Journal of Lipid Research

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and store such a large amount of cholesterol indicates that there is a close link between the evolution of the nervous system and a specifi c role for cholesterol. Within the brain, some 70% of cholesterol is present in myelin, where it fulfi lls a critical insulating role. It is likely that the requirement for effi cient signaling despite a small transverse diameter of axons was a key selective pressure driving the accretion of cholesterol in the mammalian brain ( 1, 2 ). The requirement for large amounts of cholesterol is further underscored by the long half-life of brain cholesterol; overall brain cholesterol turns over some 250-300 times slower than that in the circulation ( 3 ).At a cellular level, the myelin sheath consists of sections of plasma membrane repeatedly wrapped around an axon, with the extrusion of virtually all of the cytoplasm. Myelin is formed by 2 very specialized cells: the oligodendrocyte in the central nervous system (CNS) and the Schwann cell in the peripheral nervous system (PNS). Because an individual axon may be ensheathed by myelin from several oligodendrocytes, periodic gaps are present in the sheath. These are called the "nodes of Ranvier" and are the site of propagation of the action potential. Myelin can thus be regarded as a discontinuous insulation that enables the saltatory conduction of the action potential ( 1, 2 ). In addition Abstract Cholesterol is an essential component of both the peripheral and central nervous systems of mammals. Over the last decade, evidence has accumulated that disturbances in cholesterol metabolism are associated with the development of various neurological conditions. In addition to genetically defi ned defects in cholesterol synthesis, which will be covered in another review in this Thematic Series, defects in cholesterol metabolism (cerebrotendinous xanthomatosis) and intracellular transport (Niemann Pick Syndrome) lead to neurological disease. A subform of hereditary spastic paresis (type SPG5) and Huntington's disease are neurological diseases with mutations in genes that are of importance for cholesterol metabolism. Neurodegeneration is generally associated with disturbances in cholesterol metabolism, and presence of the E4 isoform of the cholesterol transporter apolipoprotein E as well as hypercholesterolemia are important risk factors for development of Alzheimer's disease. In the present review, we discuss the links between genetic disturbances in cholesterol metabolism and the above neurological disorders. -Björkhem, I., V. Leoni, and S. Meaney. The mammalian nervous system contains a disproportionate amount of cholesterol. In the brain, the cholesterol content is about 10-fold greater than in any other organ ( 1 ). The development of the capacity to synthesize

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

Cited by 129 publications

References 102 publications

Altered NCAM Expression Associated with the Cholinergic System in Alzheimer's Disease

Altered NCAM Expression Associated with the Cholinergic System in Alzheimer's Disease

Association of apolipoprotein E gene polymorphism with end-stage renal disease and hyperlipidemia in patients on long-term hemodialysis

Genetic connections between neurological disorders and cholesterol metabolism

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