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ApoE-dependent plasticity in Alzheimer’s disease

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Abstract

The contribution of neuroplasticity to Alzheimer’s disease (AD) is supported by important effects of apoE on both the pathology of AD and the environmental and developmental factors influencing its etiologies. The earlier age of onset of apoE4 AD patients could be caused by defects in apoE-related compensatory repair mechanisms. The role of apoE in stimulating neuronal regeneration like neurite sprouting has received much support, with apoE4 consistently showing defects both in vitro and in vivo and in AD. In addition, growing evidence indicates that the reduced sprouting activity of apoE4 represents a gain-of-negative function; that is, apoE3-stimulated sprouting increases with increasing apoE3 dose, while any neurite sprouting with apoE4 is decreased with increasing apoE4 dose. Clearly, the dose responses for all relevant apoE activities need evaluation, as well as determination of the physiologically relevant doses in the brain. Because apoE4 plays a major role in the risk and onset of AD for ∼50% of AD cases, therapies that target the mechanism of this increased risk would greatly impact AD prevalence. Possible targets include apoE expression levels and regulation, and apoE protein structure or gene replacement. The gain-of-negative function of apoE4 in neurite sprouting, or any apoE4-specific activity, could have important clinical implications for the pharmacogenetic efficacy of therapeutic drugs that impact or target apoE expression or activity. Some therapeutic drugs, including estrogen that can regulate apoE levels, show apoE isotype-dependent efficacy in AD therapy. Other candidate drugs that could modulate apoE expression include antioxidants, anti-inflammatories, and statins. The contribution of apoE4 to drug efficacy may distinguish mechanisms of disease onset from those of progression, since the pleiotropic effects of apoE and its isotypes raise the strong possibility that the isotypes differ in the mechanism by which they contribute to AD etiology.

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References

  • Alvarez X. A., Muozo R., Pichel V., Perez P., Laredo M., Fernandez-Novoa L., et al. (1999) Double-blind placebo-controlled study with citicoline in APOE genotyped Alzheimer’s disease patients. Effects on cognitive performance, brain bioelectrical activity and cerebral perfusion. Methods Findings Exp. Clin. Pharmacol. 21, 633–644.

    CAS  Google Scholar 

  • Arendt T. (2001a) Alzheimer’s disease as a disorder of mechanisms underlying structural brain self-organization. Neuroscience 102, 723–765.

    PubMed  CAS  Google Scholar 

  • Arendt T. (2001b) Disturbance of neuronal plasticity is a critical pathogenetic event in Alzheimer’s disease. Int. J. Dev. Neurosci. 19, 231–245.

    PubMed  CAS  Google Scholar 

  • Arendt T. and Zvegintseva H. (1987) Alzheimer’s disease: increase in dendritic branching of reticular neurons in basal nucleus—a sign of regeneration? in Cellular and Molecular Basis of Cholinergic Function, Dowdell, M. J., and Hawthorne, J. N., eds., VCH, Weinhem, Germany, pp. 869–873.

    Google Scholar 

  • Arendt T., Bruckner M. K., Gertz H. J., and Marcova L. (1998a) Cortical distribution of neurofibrillary tangles in Alzheimer’s disease matches the pattern of neurons that retain their capacity of plastic remodelling in the adult brain. Neuroscience 83, 991–1002.

    PubMed  CAS  Google Scholar 

  • Arendt T., Holzer M., and Gartner U. (1998b) Neuronal expression of cycline dependent kinase inhibitors of the INK4 family in Alzheimer’s disease. J. Neural Transm. 105, 949–960.

    PubMed  CAS  Google Scholar 

  • Arendt T., Schindler C., Bruckner M. K., Eschrich K., Bigl V., Zedlick D., and Marcova L. (1997) Plastic neuronal remodeling is impaired in patients with Alzheimer’s disease carrying apolipoprotein epsilon 4 allele. J. Neurosci. 17, 516–529.

    PubMed  CAS  Google Scholar 

  • Arendt T., Zvegintseva H. G., and Leontovich T. A. (1986) Dendritic changes in the basal nucleus of Meynert and in the diagonal band nucleus in Alzheimer’s disease—a quantitative Golgi investigation. Neuroscience 19, 1265–1278.

    PubMed  CAS  Google Scholar 

  • Ashford J. W. and Jarvik L. (1985) Alzheimer’s disease: does neuron plasticity predispose to axonal neurofibrillary degeneration? N. Engl. J. Med. 313, 388,389.

    PubMed  CAS  Google Scholar 

  • Ashford J. W. and Mortimer J. A. (2002) Non-familial Alzheimer’s disease is mainly due to genetic factors. J. Alzheimer’s Dis. 4, 169–177.

    Google Scholar 

  • Barres B. A. and Smith S. J. (2001) Neurobiology. Cholesterol—making or breaking the synapse. Science 294, 1296,1297.

    PubMed  CAS  Google Scholar 

  • Bassett C. N. and Montine T. J. (2003) Lipoproteins and lipid peroxidation in Alzheimers disease. J. Nutr. Health Aging 7(1), 446–451.

    Google Scholar 

  • Bellosta S., Nathan B. P., Orth M., Dong L. M., Mahley R. W., and Pitas R. E. (1995) Stable expression and secretion of apolipoproteins E3 and E4 in mouse neuroblastoma cells produces differential effects on neurite outgrowth. J. Biol. Chem. 270, 27063–27071.

    PubMed  CAS  Google Scholar 

  • Benzing W. C., Mufson E. J., and Armstrong D. M. (1993) Alzheimer’s disease-like dystrophic neurites characteristically associated with senile plaques are not found within other neurodegenerative diseases unless amyloid beta-protein deposition is present. Brain Res. 606, 10–18.

    PubMed  CAS  Google Scholar 

  • Bertoni-Freddari C. (1988) Age-dependent deterioration of neuronal membranes and the pathogenesis of Alzheimer’s disease: a hypothesis. Med. Hypotheses 25, 147–149.

    PubMed  CAS  Google Scholar 

  • Blacker D., Haines J. L., Rodes L., Terwedow H., Go R. C. P., Harrell L. E., et al. (1997) ApoE-4 and age at onset of Alzheimer’s disease: the NIMH genetics initiative. Neurology 48, 139–147.

    PubMed  CAS  Google Scholar 

  • Boyles J. K., Zoellner C. D., Anderson L. J., Kosik L. M., Pitas R. E., Weisgraber K. H., et al. (1989) A role for apolipoprotein E, apolipoprotein A-I, and low density lipoprotein receptors in cholesterol transport during regeneration and remyelination of the rat sciatic nerve. J. Clin. Invest. 83, 1015–1031.

    PubMed  CAS  Google Scholar 

  • Bretsky P. M., Buckwalter J. G., Seeman T. E., Miller C. A., Poirier J., Schellenberg G. D., et al. (1999) Evidence for an interaction between apolipoprotein E genotype, gender, and Alzheimer disease. Alzheimer Dis. Assoc. Disord. 13, 216–221.

    PubMed  CAS  Google Scholar 

  • Bruses J. L., Chauvet N., and Rutishauser U. (2001) Membrane lipid rafts are necessary for the maintenance of the (alpha)7 nicotinic acetylcholine receptor in somatic spines of ciliary neurons. J. Neurosci. 21, 504–512.

    PubMed  CAS  Google Scholar 

  • Buttini M., Akeefe H., Lin C., Mahley R. W., Pitas R. E., Wyss-Coray T., and Mucke L. (2000) Dominant negative effects of apolipoprotein E4 revealed in transgenic models of neurodegenerative disease. Neuroscience 97, 207–210.

    PubMed  CAS  Google Scholar 

  • Buttini M., Orth M., Bellosta S., Akeefe H., Pitas R. E., Wyss-Coray T., et al. (1999) Expression of human apolipoprotein ε3 or ε4 in the brains of apoe-/- mice: isoform-specific effects on neurodegeneration. J. Neurosci. 19, 4867–4880.

    PubMed  CAS  Google Scholar 

  • Buxbaum J. D., Cullen E. I., and Friedhoff L. T. (2002) Pharmacological concentrations of the HMG-CoA reductase inhibitor lovastatin decrease the formation of the Alzheimer beta-amyloid peptide in vitro and in patients. Front. Biosci. 7, a50-a59.

    PubMed  CAS  Google Scholar 

  • Cambon K., Davies H. A., and Stewart M. G. (2000) Synaptic loss is accompanied by an increase in synaptic area in the dentate gyrus of aged human apolipoprotein E4 transgenic mice. Neuroscience 97, 685–692.

    PubMed  CAS  Google Scholar 

  • Cassell M. D. and Brown M. W. (1984) Distribution of timm’s stain in the nonsulphide-perfused human hippocampal formation. J. Comp. Neurol. 222, 461–471.

    PubMed  CAS  Google Scholar 

  • Chawen J. A., Torres-Aleman I., and Garcia-Segura L. M. (1992) Trophic effects of estradiol on fetal rat hypothalamic neurons. Neuroendocrinology 56, 895–901.

    Google Scholar 

  • Chen Y., Lomnitski L., Michaelson D. M., and Shohami E. (1997) Motor and cognitive deficits in apolipoprotein E-deficient mice after closed head injury. Neuroscience 80(4), 1255–1262.

    PubMed  CAS  Google Scholar 

  • Corder E. H., Saunders A. M., Strittmatter W. J., Schmechel D. E., Gaskell P. C., Small G. W., et al. (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921–923.

    PubMed  CAS  Google Scholar 

  • Cotman C. W., Cummings B. J., and Pike C. J. (1993) Molecular cascades in adaptive versus pathological plasticity. Raven Press, New York.

    Google Scholar 

  • Cotman C. W., Cummings B. J., and Whitson J. S. (1991) The role of misdirected plasticity in plaque biogenesis and Alzheimer’s disease pathology., in Growth Factors and Alzheimer’s Disease, Hefti, F., Brachet, B., and Christen, W. Y., eds., Springer-Verlag, Berlin, pp. 222–233.

    Google Scholar 

  • Danik M. and Poirier J. (1998) Apolipoprotein E and neuronal plasticity following experimental deafferentation and in Alzheimer’s disease. Biochem. Soc. Trans. 26, 262–266.

    PubMed  CAS  Google Scholar 

  • DeMattos R. B., Brendza R. P., Heuser J. E., Kierson M., Cirrito J. R., Fryer J., et al. (2001) Purification and characterization of astrocyte-secreted apolipoprotein E and J-containing lipoproteins from wild-type and human apoE transgenic mice. Neurochem. Int. 39, 415–425.

    PubMed  CAS  Google Scholar 

  • DeMattos R. B., Curtiss L. K. and Williams D. L. (1998) A minimally lipidated form of cell-derived apolipoprotein E exhibits isoform-specific stimulation of neurite outgrowth in the absence of exogenous lipids or lipoproteins. J. Biol. Chem. 273, 4206–4212.

    PubMed  CAS  Google Scholar 

  • Dietschy J. M. and Turley S. D. (2001) Cholesterol metabolism in the brain. Curr. Opin. Lipidol. 12, 105–12.

    PubMed  CAS  Google Scholar 

  • Fagan A. M., Bu G., Sun Y., Daugherty A., and Holtzman D. M. (1996) Apolipoprotein E-containing high density lipoprotein promotes neurite outgrowth and is a ligand for the low density lipoprotein receptor-related protein. J. Biol. Chem. 271, 30121–30125.

    PubMed  CAS  Google Scholar 

  • Fagan A. M., Murphy B. A., Patel S. N., Kilbridge J. F., Mobley W. C., Bu G., and Holtzman D. M. (1998) Evidence for normal aging of the septo-hippocampal cholinergic system in apoE (-/-) mice but impaired clearance of axonal degeneration products following injury. Exp. Neurol. 151, 314–325.

    PubMed  CAS  Google Scholar 

  • Farlow M. R., Lahiri D. K., Poirier J., Davignon J., et al. (1998) Treatment outcome of tacrine therapy depends on apolipoprotein genotype and gender of the subjects with Alzheimer’s disease. Neurology 50(3), 669–677.

    PubMed  CAS  Google Scholar 

  • Farrer L. A., Cupples L. A., Haines J. L., Hyman B., Kukull W. A., Myers R. H., and van Duijin C. M. (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer’s Disease Meta Analysis Consortium. JAMA 278, 1349–1356.

    PubMed  CAS  Google Scholar 

  • Farrer L. A., Cupples L. A., van Duijn C. M., Kurz A., Zimmer R., Muller U., et al. (1995) Apolipoprotein E genotype in patients with Alzheimer’s disease: implications for the risk of dementia among relatives. Ann. Neurol. 38, 797–808.

    PubMed  CAS  Google Scholar 

  • Fernandes M. A., Proenca M. T., Nogueira A. J., Oliveira L. M., Santiago B., Santana I., and Oliveira C. R. (1999) Effects of apolipoprotein E genotype on blood lipid composition and membrane platelet fluidity in Alzheimer’s disease. Biochim. Biophys. Acta 1454, 89–96.

    PubMed  CAS  Google Scholar 

  • Ferrer I., Guionnet N., Cruz-Sanchez F., and Tunon T. (1990) Neuronal alterations in patients with dementia: a Golgi study on biopsy samples. Neurosci. Lett. 114, 11–16.

    PubMed  CAS  Google Scholar 

  • Feussner G., Dobmeyer J., Grone H. J., Lohmer S., and Wohlfeil S. (1996) A 10-bp deletion in the apolipoprotein epsilon gene causing apolipoprotein E deficiency and severe type III hyperlipoproteinemia. Am. J. Hum. Genet. 58, 281–291.

    PubMed  CAS  Google Scholar 

  • Fischer O. (1907) Miliare necrosen mit drusigen wucherungen der neurofibrillen, eine regelmassige veranderung der hirnrinde bei seniler demenz. Psychiatrie Neurol. 22, 361–372.

    Article  Google Scholar 

  • Gaarskjaer F. B. (1986) The organization and development of the hippocampal mossy fiber system. Brain Res. Rev. 11, 335–357.

    Google Scholar 

  • Geddes J. W., Lundgren K., and Kim Y. K. (1991) Aberrant localization of MAP5 immunoreactivity in the hippocampal formation in Alzheimer’s disease. J. Neurosci. Res. 30, 183–191.

    PubMed  CAS  Google Scholar 

  • Geddes J. W., Monaghan D. T., Cotman C. W., Lott I. T., Kim R. C., and Chui H. C. (1985) Plasticity of hippocampal circuitry in Alzheimer’s disease. Science 230, 1179–1181.

    PubMed  CAS  Google Scholar 

  • Gimpl G., Burger K., and Fahrenholz F. (1997) Cholesterol as modulator of receptor function. Biochemistry 36, 10959–10974.

    PubMed  CAS  Google Scholar 

  • Gonatas N. K., Anderson W., and Evangelista I. (1967) The contribution of altered synapses in the senile plaque: an electron microscopic study in Alzheimer’s dementia. J. Neuropathol. Exp. Neurol. 2, 25–39.

    Google Scholar 

  • Gottfries C. G., Karlsson I., and Svennerholm L. (1996) Membrane components separate early-onset Alzheimer’s disease from senile dementia of the Alzheimer type. Int. Psychogeriatr. 8, 365–372.

    PubMed  CAS  Google Scholar 

  • Handelmann G. E., Boyles J. K., Weisgraber K. H., Mahley R. W., and Pitas R. E. (1992) Effects of apolipoprotein E, β-very low density lipoproteins, and cholesterol on the extension of neurites by rabbit dorsal root ganglion neurons in vitro. J. Lipid Res. 33, 1677–1688.

    PubMed  CAS  Google Scholar 

  • Heininger K. (2000) A unifying hypothesis of Alzheimer’s disease. IV. Causation and sequence of events. Rev. Neurosci. 11, 213–328.

    PubMed  Google Scholar 

  • Herz J. (2001) The LDL receptor gene family: (un)expected signal transducers in the brain. Neuron 29, 571–581.

    PubMed  CAS  Google Scholar 

  • Hesse C., Larsson H., Fredman P., Minthon L., Andreasen N., Davidsson P., and Blennow K. (2000) Measurement of apolipoprotein E (apoE) in cerebrospinal fluid. Neurochem. Res. 25, 511–517.

    PubMed  CAS  Google Scholar 

  • Hoffman P. W. and Chernak J. M. (1994) The rat amyloid precursor protein promoter contains two DNA regulatory elements which influence high level gene expression. Biochem. Biophys. Res. Commun. 201, 610–617.

    PubMed  CAS  Google Scholar 

  • Holtzman D. M. and Fagan A. M. (1998) Potential role of apoE in structural plasticity in the nervous system—implications for disorders of the central nervous system. Trends Cardiovasc. Med. 8, 250–255.

    PubMed  CAS  Google Scholar 

  • Holtzman D. M., Pitas R. E., Kilbridge J., Nathan B., Mahley R. W., Bu G., and Schwartz A. L. (1995) Low density lipoprotein receptor-related protein mediates apolipoprotein E-dependent neurite outgrowth in a central nervous system-derived neuronal cell line. Proc. Natl. Acad. Sci. USA 92, 9480–9484.

    PubMed  CAS  Google Scholar 

  • Huang D. Y., Weisgraber K. H., Strittmatter W. J., and Matthew W. D. (1995) Interaction of Apolipoprotein E with laminin increases neuronal adhesion and alters neurite morphology. Exp. Neurol. 136, 251–257.

    PubMed  CAS  Google Scholar 

  • Huang D. Y., Liu X. Q., and Mahley R. W. (1999) Differential effects of cytosolic apolipoprotein (APO) E3 and ApoE4 on neurite outgrowth. c. Neurosci. Abstr. 16.4.

  • Hyman B. T., Gomez-Isla T., Rebeck G. W., Briggs M., Chung H., West H. L., et al. (1996) Epidemiological, clinical, and neuropathological study of apolipoprotein E genotype in Alzheimer’s disease. Ann. NY Acad. Sci. 802, 1–5.

    PubMed  CAS  Google Scholar 

  • Ihara Y. (1988) Massive somatodendritic sprouting of cortical neurons in Alzheimer’s disease. Brain Res. 459, 138–144.

    PubMed  CAS  Google Scholar 

  • Ji Z. S., Pitas R. E., and Mahley R. W. (1998) Differential cellular accumulation/retention of apolipoprotein E mediated by cell surface heparan sulfate proteoglycans. Apolipoproteins E3 and E2 greater than E4. J. Biol. Chem. 273, 13452–13460.

    PubMed  CAS  Google Scholar 

  • Jick H., Zornberg G. L., Jick S. S., Seshadri S., and Drachman D. A. (2000) Statins and the risk of dementia. Lancet 356, 1627–1631.

    PubMed  CAS  Google Scholar 

  • Johannsson G., Oscarsson J., Rosen T., Wiklund O., Olsson G., Wilhelmsen L., and Bengtsson B. A. (1995) Effects of growth hormone therapy on serum lipoprotein levels in growth hormone deficient adults. Influence of gender and apo(A) and apoE phenotypes. Arter. Thromb. Vasc. Biol. 15(12), 2142–2150.

    CAS  Google Scholar 

  • Jordan J., Galindo M. F., Miller R. J., Reardon C. A., Getz G. S., and LaDu M. J. (1998) Isoform-specific effect of apolipoprotein E on cell survival and beta-amyloid-induced toxicity in rat hippocampal pyramidal neuronal cultures. J. Neurosci. 18, 195–204.

    PubMed  CAS  Google Scholar 

  • Joseph J., Shukitt-Hale B., Denisova N. A., Martin A., Perry G., and Smith M. A. (2001) Copernicus revisited: amyloid beta in Alzheimer’s disease. Neurobiol. Aging 22, 131–146.

    PubMed  CAS  Google Scholar 

  • Kerr M. E. and Kraus M. (1998) Genetics and the central nervous system: apolipoprotein E and brain injury. AACN Clin. Issues 9, 524–530.

    Article  PubMed  CAS  Google Scholar 

  • Kivatinitz S. C., Pelsman M. A., Alonso A. C., Bagatolli L., and Quiroga S. (1997) High-density lipoprotein aggregated by oxidation induces degeneration of neuronal cells. J. Neurochem. 69, 2102–2114.

    Article  PubMed  CAS  Google Scholar 

  • Kosik K. (1992) Alzheimer’s disease: A cell biological perspective. Science 256, 780–783.

    PubMed  CAS  Google Scholar 

  • Koudinov A. R. and Koudinova N. V. (2001) Essential role for cholesterol in synaptic plasticity and neuronal degeneration. FASEB J. 15, 1858–1860.

    PubMed  CAS  Google Scholar 

  • Kushwaha R. S., Foster D. M., Barrett P. H., Carey K. D., and Bernard M. G. (1991) Metabolic regulation of plasma apolipoprotein E by estrogen and progesterone in the baboon (Papio sp.). Metabolism 40, 93–100.

    PubMed  CAS  Google Scholar 

  • LaDu M. J., Reardon C., Van Eldik L., Fagan A. M., Bu G., Holtzman D., and Getz G. S. (2000) Lipoproteins in the central nervous system. Ann. NY Acad. Sci. 903, 167–175.

    PubMed  CAS  Google Scholar 

  • Lang T., Bruns D., Wenzel D., Riedel D., Holroyd P., Thiele C., and Jahn R. (2001) SNAREs are concentrated in cholesterol-dependent clusters that define docking and fusion sites for exocytosis. EMBO J. 20, 2202–2213.

    PubMed  CAS  Google Scholar 

  • Laskowitz D. T., Horsburgh K., and Roses A. D. (1998) Apolipoprotein E and the CNS response to injury. J. Cerebr. Blood Flow Metab. 18, 465–471.

    CAS  Google Scholar 

  • Laskowitz D. T., Sheng H., Bart R., Joyner K. A., Roses A. D., and Warner D. S. (1997) Apolipoprotein E-deficient mice have increased susceptibility to focal ischemia. J. Cerebr. Blood Flow Metab. 17, 753–758.

    CAS  Google Scholar 

  • Le Bars P. L., Katz M. M., Berman N., Itil T. M., Freedman A. M., and Schatzberg A. F. (1997) A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. JAMA 278, 1327–1332.

    PubMed  Google Scholar 

  • Locatelli S., Lutjohann D., Schmidt H. H., Otto C., Beisiegel U., and von Bergmann K. (2002) Reduction of plasma 24S-hydroxycholesterol (cerebrosterol) levels using high-dosage simvastatin in patients with hypercholesterolemia: evidence that simvastatin affects cholesterol metabolism in the human brain. Arch. Neurol. 59, 213–216.

    PubMed  Google Scholar 

  • MacGowan S. H., Wilcock G. K., and Scott M. (1998) Effect of gender and apolipoprotein E genotype on response to anticholinesterase therapy in Alzheimer’s disease. Int. J. Geriatr. Psychiatry 13, 625–630.

    PubMed  CAS  Google Scholar 

  • Mahley R. W. (1988) Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 240, 622–630.

    PubMed  CAS  Google Scholar 

  • Mahley R. and Huang Y. (1999) Apolipoprotein E: from atherosclerosis to Alzheimer’s disease and beyond. Curr. Opin. Lipidol. 10, 207–217.

    PubMed  CAS  Google Scholar 

  • Mahley R. W. and Rall S. C., Jr. (2000) Apolipoprotein E: far more than a lipid transport protein. Annu. Rev. Genomics Hum. Genet. 1, 507–537.

    PubMed  CAS  Google Scholar 

  • Majocha R. E., Jungalwala F. B., Rodenrys A., and Marotta C. A. (1989) Monoclonal antibody to embryonic CNS antigen A2B5 provides evidence for the involvement of membrane components at sites of Alzheimer degeneration and detects sulfatides as well as gangliosides. J. Neurochem. 53, 953–961.

    PubMed  CAS  Google Scholar 

  • Marques M. A., Harmony J. A., and Crutcher K. A. (1996) A thrombin cleavage fragment of apolipoprotein E and related synthetic peptides is receptor-mediated. Neuroreport 7, 2529–2532.

    PubMed  CAS  Google Scholar 

  • Martens J. R., Navarro-Polanco R., Coppock E. A., Nishiyama A., Parshley L., Grobaski T. D., and Tamkun M. M. (2000) Differential targeting of Shaker-like potassium channels to lipid rafts. J. Biol. Chem. 275, 7443–7446.

    PubMed  CAS  Google Scholar 

  • Masliah E., Mallory M., De Teresa R., Alford M., and Hansen L. (1993a) Differing patterns of aberrant neuronal sprouting in Alzheimer’s disease with and without Lewy bodies. Brain Res. 617, 258–266.

    PubMed  CAS  Google Scholar 

  • Masliah E., Miller A., and Terry R. D. (1993b) The synaptic organization of the neocortex in Alzheimer’s disease. Med. Hypotheses 41, 334–340.

    PubMed  CAS  Google Scholar 

  • Masliah E., Mallory M., Alford M., Ge N., and Mucke L. (1995a) Abnormal synaptic regeneration in hAPP695 transgenic and ApoE knockout mice, in Research Advances in Alzheimer’s Disease and Related Disorders, Iqbal, K., Mortimer, J., Winblad, B., and Wisniewski, H. M., eds., Wiley, Chichester, UK, pp. 405–414.

    Google Scholar 

  • Masliah E., Mallory M., Alford M., Veinbergs I., and Roses A. D. (1995b) Apolipoprotein E role in maintaining the integrity of the aging central nervous system. Apolipoprotein E and Alzheimer’s Disease, Christian Y. and Roses A.D., eds.), Springer, New York.

    Google Scholar 

  • Masliah E., Mallory M., Ge N., Alford M., Veinbergs I., and Roses A. D. (1995c) Neurodegeneration in the central nervous system of ApoE-deficient mice. Exp. Neurol. 136, 107–122.

    PubMed  CAS  Google Scholar 

  • Masliah E., Mallory M., Ge N., and Mucke L. (1995d) Synaptic regeneration in hAPP695 transgenic and APOE knockout mice. Neuropathology 44, 405–414.

    Google Scholar 

  • Masliah E., Mallory M., Veinbergs I., Miller A., and Samuel W, (1996) Alterations in apolipoprotein E expression during aging and neurodegeneration. Prog. Neurobiol. 50, 493–503.

    PubMed  CAS  Google Scholar 

  • Masliah E., Samuel W., Veinbergs I., Mallory M., Mante M., and Saitoh T. (1997) Neurodegeneration and cognitive impairment in apoE-deficient mice is ameliorated by infusion of recombinant apoE. Brain Res. 751, 307–314.

    PubMed  CAS  Google Scholar 

  • Masliah E., Armasolo F., Veinbergs I., Mallory M., and Samuel W. (1999) Cerebrolysin ameliorates performance deficits, and neuronal damage in apolipoprotein E-deficient mice. Pharmacol. Biochem. Behav. 62, 239–245.

    PubMed  CAS  Google Scholar 

  • Mason R. P., Shoemaker W. J., Shajenko L., Chambers T. E., and Herbette L. G. (1992) Evidence for changes in the Alzheimer’s disease brain cortical membrane struture mediated by cholesterol. Neurobiol. Aging 13, 413–419.

    PubMed  CAS  Google Scholar 

  • Mauch D. H., Nagler K., Schumacher S., Gorits C., Muller E.-C., Otto A., and Pfrieger F. W. (2001) CNS synaptogenesis promoted by glial-derived cholesterol. Science 294, 1354–1357.

    PubMed  CAS  Google Scholar 

  • McKee A. C., Kowall N. W., and Kosik K. S. (1989) Microtubular reorganization and dendritic growth response in Alzheimer’s disease. Ann. Neurol. 26, 652–659.

    PubMed  CAS  Google Scholar 

  • Mesulam M. M. (1999) Neuroplasticity failure in Alzheimer’s disease: bridging the gap between plaques and tangles. Neuron 24, 521–529.

    PubMed  CAS  Google Scholar 

  • Mesulam M. M. (2000) A plasticity-based theory of the pathogenesis of Alzheimer’s disease. Ann. N. Y. Acad. Sci. 924, 42–52.

    Article  PubMed  CAS  Google Scholar 

  • Meyer M. R. (1998) APOE genotype predicts when—not whether—one is predisposed to develop Alzheimer disease. Nat. Genet. 19, 321–322.

    PubMed  CAS  Google Scholar 

  • Miranda P., Williams C. L., and Einstein G. (1999) Granule cells are sexually dimorphic in their response to estradiol. J. Neurosci. 19, 3316–3325.

    PubMed  CAS  Google Scholar 

  • Muesing R. A., Miller V. T., LaRosa J. C., Stoy D. B., and Phillips E. A, (1992) Effects of unopposed conjugated equine estrogen on lipoprotein composition and apolipoprotein-E distribution. J. Clin. Endocrinol. Metab. 75, 1250–1254.

    PubMed  CAS  Google Scholar 

  • Mulder M., Ravid R., Swaab D. F., de Kloet E. R., Haasdijk E. D., Julk J., et al. (1998) Reduced levels of cholesterol, phospholipids, and fatty acids in cerebrospinal fluid of Alzheimer disease patients are not related to apolipoprotein E4. Alzheimer Dis. Assoc. Disord. 12, 198–203.

    PubMed  CAS  Google Scholar 

  • Muller H. W., Gebicke-Harter P. J., Hangen D. H., and Shooter E. M. (1997) A specific 37,000-Dalton protein that accumulates in regenerating but not in nongenerating mammalian nerves. Science 228, 499–501.

    Google Scholar 

  • Nathan B. P., Bellosta S., Sanan D. A., Weisgraber K. H., Mahley R. W., and Pitas R. E. (1994) Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro. Science 264, 850–852.

    PubMed  CAS  Google Scholar 

  • Nathan B. P., Chang K., Bellosta S., Brisch E., Ge N., Mahley R. W., and Pitas R. E. (1995) The inhibitory effect of apolipoprotein E4 on neurite outgrowth is associated with microtubule depolymerization. J. Biol. Chem. 270(34), 19791–19799.

    PubMed  CAS  Google Scholar 

  • Nathan B. P., Jiang Y., Wong G. K., Shen F., Brewer G., and Struble R. G. (2002) Apolipoprotein E4 inhibits, and apolipoprotein E3 promotes neurite sprouting in cultured adult mouse cortical neurons through a low-density lipoprotin receptor-related protein. Brain Res. 928, 96–105.

    PubMed  CAS  Google Scholar 

  • Neely M. D. and Montine T. J. (2002) CSF lipoproteins and Alzheimer’s disease. J. Nutr. Health Aging 6(6), 383–391.

    PubMed  CAS  Google Scholar 

  • Neely M. D., Sidell K. R., Graham D. G., and Montine T. J. (1999) The lipid peroxidation product 4-hydroxynonenal inhibits neurite outgrowth, disrupts neuronal microtubules and modifies cellular tubulin. J. Neurochem. 72, 2323–2333.

    PubMed  CAS  Google Scholar 

  • Neill D. (1995) Alzheimer’s disease: maladaptive synaptoplasticity hypothesis. Neurodegeneration 4, 217–232.

    PubMed  CAS  Google Scholar 

  • Pfrieger F. W. and Barres B. A. (1997) Synaptic efficacy enhanced by glial cells in vitro. Science 277, 1684–1687.

    PubMed  CAS  Google Scholar 

  • Phinney A. L., Deller T., Stalder M., Calhoun M. E., Frotscher M., Sommer B., et al. (1999) Cerebral amyloid induces aberrant axonal sprouting and ectopic terminal formation in amyloid precursor protein transgenic mice. J. Neurosci. 19, 8552–8559.

    PubMed  CAS  Google Scholar 

  • Pitas R. E. (1996) Microtubule formation and neurite extension are blocked by apolipoprotein E4. Semin. Cell Biol. 7, 725–731.

    CAS  Google Scholar 

  • Pitas R. E., Ji Z. S., Weisgraber K. H., and Mahley R. W. (1998) Role of apolipoprotein E in modulating neurite outgrowth: potential effect of intracellular apolipoprotein E. Biochem. Soc. Trans. 26, 257–262.

    PubMed  CAS  Google Scholar 

  • Poirier J. (1994) Apolipoprotein E in animal models of CNS injury and in Alzheimer’s disease. Trends Neurosci. 17, 525–530.

    PubMed  CAS  Google Scholar 

  • Poirier J. (1999) Apolipoprotein E: a pharmacogenetic target for the treatment of Alzheimer’s disease. Mol. Diagn. 4, 335–341.

    PubMed  CAS  Google Scholar 

  • Poirier J., Baccichet D. D., and Gauthier S. (1993a) Cholesterol synthesis and lipoprotein reuptake during synaptic remodeling in hippocampus in adult rats. Neuroscience 55, 81–90.

    PubMed  CAS  Google Scholar 

  • Poirier J., Davignon J., Bouthillier D., Kogan S., Bertrand P., and Gauthier S. (1993b) Apolipoprotein E polymorphism and Alzheimer’s disease. Lancet 342, 697–699.

    PubMed  CAS  Google Scholar 

  • Poirier J., Delisle M.-C., Quirion R., Aubert I., Farlow M., Lahiri D., et al. (1995a) Apolipoprotein E4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer disease. Proc. Natl. Acad. Sci. USA 92, 12260–12264.

    PubMed  CAS  Google Scholar 

  • Poirier J., Minnich A., and Davignon J. (1995b) Apolipoprotein E, synaptic plasticity and Alzheimer’s disease. Ann. Med. 27, 663–670.

    PubMed  CAS  Google Scholar 

  • Popko B., Goodrum J. F., Bouldin T. W., Zhang S. H., and Maeda N. (1993) Nerve regeneration occurs in the absence of apolipoprotein E in mice. J. Neurochem. 60, 1155–1158.

    PubMed  CAS  Google Scholar 

  • Posse de Chaves E. I., Rusinol A. E., Vance D. E., Campenot R. B., and Vance J. E. (1997) Role of lipoproteins in the delivery of lipids to axons during axonal regeneration. J. Biol. Chem. 272, 30766–30773.

    Google Scholar 

  • Probst A., Basler V., Bron B., and Ulrich J. (1983) Neuritic plaques in senile dementia of Alzheimer type: a Golgi analysis in the hippocampal region. Brain Res. 268, 249–254.

    PubMed  CAS  Google Scholar 

  • Puttfarcken P. S., Manelli A. M., Falduto M. T., Getz G. S., and LaDu M,-J. (1997) Effect of apolipoprotein E on neurite outgrowth and β-amyloid-induced toxicity in developing rat primary hippocampal cultures. J. Neurochem. 68, 760–769.

    Article  PubMed  CAS  Google Scholar 

  • Raber J., Bongers G., LeFevour A., Buttini M., and Mucke L. (2002) Androgens protect against apolipoprotein E4-induced cognitive deficits. J. Neurosci. 22, 5204–5209.

    PubMed  CAS  Google Scholar 

  • Raber J., Wong D., Buttini M., Orth M., Bellosta S., Pitas R. E., et al. (1998) Isoform-specific effects of human apolipoprotein E on brain function revealed in apoe knockout mice: increased susceptibility of females. Proc. Natl. Acad. Sci. USA 95, 10914–10919.

    PubMed  CAS  Google Scholar 

  • Raber J., Wong D., Yu G.-Q., Buttini M., Mahley R. W., Pitas R. E., and Mucke L. (2000) Apolipoprotein E and cognitive performance. Nature 404, 352–384.

    PubMed  CAS  Google Scholar 

  • Ramassamy C., Averill D., Beffert U., Theroux L., Lussier-Cacan S., and Cohn J. S. (2000) Oxidative insults are associated with apolipoprotein E genotype in Alzheimer’s disease brain. Neurobiol. Dis. 7, 23–37.

    PubMed  CAS  Google Scholar 

  • Rapoport S. I. (2001) In vivo fatty acid incorporation into brain phosholipids in relation to plasma availability, signal transduction and membrane remodeling. J. Mol. Neurosci. 16, 243–261; (Discussion) 279–284.

    PubMed  CAS  Google Scholar 

  • Rice D. S., Nusinowitz S., Azimi A. M., Martinez A., Soriano E., and Curran T. (2001) The reelin pathway modulates the structure and function of retinal synaptic circuitry. Neuron 313, 929–941.

    Google Scholar 

  • Richard F., Helbecque N., Neuman E., Guez D., Levy R., and Amouyel P. (1997) ApoE genotyping and response to drug treatment in Alzheimer’s disease. Lancet 349, 539.

    PubMed  CAS  Google Scholar 

  • Rockwood K., Kirkland S., Hogan D. B., MacKnight C., Merry H., Verreault R., et al. (2002) Use of lipid-lowering agents, indication bias, and the risk of dementia in community-dwelling elderly people. Arch. Neurol. 59, 223–227.

    PubMed  Google Scholar 

  • Roses A. D. and Saunders A. M. (1997) Lipid metabolism in the brain: a truly undeveloped science, in Cerebrovascular Pathology in Alzheimer’s Disease, de la Torre, J. C., and Hachinski, V., eds., New York Academy of Sciences, New York, p. 208.

    Google Scholar 

  • Roses A. D., Einstein G., Gilbert J., Goedert M., Han S. H., Huang D., et al. (1996) Morphological, biochemical, and genetic support for an apolipoprotein E effect on microtubular metabolism. Ann. NY Acad. Sci. 777, 147–157.

    Google Scholar 

  • Sano M., Ernesto C., Thomas R. G., Klauber M. R., Schafer K., Grundman M., et al. (1997) A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. N. Engl. J. Med. 336, 1216–1222.

    PubMed  CAS  Google Scholar 

  • Saunders A. M., Trowers M. K., Shimkets R. A., Blakemore S., Crowther D. J., Mansfield T. A., et al. (2000) The role of apolipoprotein E in Alzheimer’s disease: pharmacogenomic target selection. Biochim. Biophys. Acta 1502, 85–94.

    PubMed  CAS  Google Scholar 

  • Scheibel A. B. and Tomiyasu U. (1978) Dendritic sprouting in Alzheimer’s presentile dementia. Exp. Neurol. 60, 1–8.

    PubMed  CAS  Google Scholar 

  • Schneider L. S. and Farlow M. (1997) Combined tacrine and estrogen replacement therapy in patients with Alzheimer’s disease. Ann. NY Acad. Sci. 826, 317–322.

    PubMed  CAS  Google Scholar 

  • Scott R. B., Collins J. M., and Hunt P. A. (1994) Alzheimer’s disease and Down syndrome: leukocyte membrane fluidity alterations. Mech. Ageing Dev. 75, 1–10.

    PubMed  CAS  Google Scholar 

  • Sekiguchi M., Abe H., Nagato Y., Tanaka O., Guo H., and Nowakowski R. S. (1996) The abnormal distribution of mossy fiber bundles and morphological abnormalities in hippocampal formation of dreher-J (dr-J/dr-J) mouse. Dev. Brain Res. 92, 31–38.

    CAS  Google Scholar 

  • Simchowicz T. (1911) Histologic studien uber die senile demenz, in Histologische und Histopathologische arbeiten uber die grosshirnrinde mit besonderer berucksichtigung der pathologischen anatomie der geistekrankheiten, Nissl, F. and Alzheimer, A., eds., Fischer, Jena, Germany, pp. 267–444.

    Google Scholar 

  • Sjoberg A., Oscarsson J., Eden S., and Olofsson S. O. (1994) Continuous but not intermittent administration of growth hormone to hypophysectomized rats increases apolipoprotein-E secretion from cultured hepatocytes. Endocrinology 134, 790–798.

    PubMed  CAS  Google Scholar 

  • Slomianka L. and Geneser F. A. (1997) Postnatal development of zinc-containing cells and neuropil in the hippocampal region of the mouse. Hippocampus 7(3), 321–340.

    PubMed  CAS  Google Scholar 

  • Smith J. D., Miyata M., Poulin S. E., Neveux L. M., and Craig W. Y. (1998) The relationship between apolipoprotein E and serum oxidation-related variables is apolipoprotein E phenotype dependent. Int. J. Clin. Lab. Res. 28(2), 116–121.

    PubMed  CAS  Google Scholar 

  • Stone D. J., Rozovsky I, Morgan T. E., Anderson C. P., and Finch C. E. (1998) Increased synaptic sprouting in response to estrogen via an apolipoprotein E-dependent mechanism: implications for Alzheimer’s disease. J. Neurosci. 18(9), 3180–3185.

    PubMed  CAS  Google Scholar 

  • Stone D. J., Rozovsky I., Morgan T. E., Anderson C. P., Hajian H., and Finch C. E. (1997) Astrocytes and microglia respond to estrogen with increased apoE mRNA in vivo and in vitro. Exp. Neurol. 143, 313–318.

    PubMed  CAS  Google Scholar 

  • Su J. H., Cummings B. J., and Cotman C. W. (1993) Identification and distribution of axonal dystrophic neurites in Alzheimer’s disease. Brain Res. 625, 228–237.

    PubMed  CAS  Google Scholar 

  • Sun Y., Wu S., Bu G., Onifade M. K., Patel S. N., LaDu M. J., Fagan A. M., and Holtzman D. M. (1998) Glial fibrillary acidic protein-apolipoprotein E transgenic mice: astrocyte-specific expression and differing biological effects of astrocyte-secreted apoE3 and apoE4 lipoproteins. J. Neurosci. 18, 3261–3272.

    PubMed  CAS  Google Scholar 

  • Svennerholm L. and Gottfries C. G. (1994) Membrane lipids, selectively diminished in Alzheimer brains, suggest synapse loss as a primary event in early-onset form (type I) and demyelination in late-onset form (type II). J. Neurochem. 62, 1039–1047.

    Article  PubMed  CAS  Google Scholar 

  • Teter B., Harris-White M., Frautschy S. A., and Cole G. M. (1999) Role of Apolipoprotein E and estrogen in mossy fiber sprouting in hippocampal slice cultures. Neuroscience 91, 1009–1016.

    PubMed  CAS  Google Scholar 

  • Teter B., Xu P.-T., Gilbert J. R., Roses A. D., Galasko D., and Cole G. M. (1999) Human apolipoprotein E isoform-specific differences in neuronal sprouting in organotypic hippocampal culture. J. Neurochem. 73, 2613–2616.

    PubMed  CAS  Google Scholar 

  • Teter B. (2000) Apolipoprotein E isotype-specific effects in neurodegeneration. Alzheimer Rep. 3, 199–212.

    Google Scholar 

  • Teter B. and Ashford J. W. (2002) Neuroplasticity in Alzheimer’s disease. J. Neurosci. Res. 70(3), 402–437.

    PubMed  CAS  Google Scholar 

  • Teter B., Raber J., Nathan B., and Crutcher K. A. (2002a) The presence of apoE4, not the absence of apoE3, contributes to AD pathology. J. Alzheimer’s Dis. 4, 155–163.

    CAS  Google Scholar 

  • Teter B., Xu P.-T., Gilbert J. R., Roses A. D., Galasko D., and Cole G. M. (2002b) Defective neuronal sprouting supported by human Apolipoprotein E4 represents again-of-deleterious function. J. Neurosci. Res. 68, 331–336.

    PubMed  CAS  Google Scholar 

  • Therond P., Bonnefont-Rousselot D., Laureaux C., Vasson M. P., Motta C., Legrand A., and Delattre J. (1999) Copper oxidation of in vitro dioleolylphosphatidyl-choline-enriched high-density lipoproteins: physicochemical features and cholesterol effluxing capacity. Arch. Biochem. Biophys. 362(1), 139–147.

    PubMed  CAS  Google Scholar 

  • Thiele C., Hannah M. J., Fahrenholz F., and Huttner W. B. (2000) Cholesterol binds to synaptophysin and is required for biogenesis of synaptic vesicles. Nat. Cell Biol. 2, 42–49.

    PubMed  CAS  Google Scholar 

  • Ullian E. M., Sapperstein S. K., Christopherson K. S., and Barres B. A. (2001) Control of synapse number by glia. Science 291, 657–660.

    PubMed  CAS  Google Scholar 

  • Vance J. E., Campenot R. B., and Vance D. E. (2000) The synthesis and transport of lipids for axonal growth and nerve regeneration. Biochim. Biophys. Acta 1486, 84–96.

    PubMed  CAS  Google Scholar 

  • Veinbergs I., Mallory M., Mante M., Rockenstein E., Gilbert J. R., and Masliah E. (1999) Differential neurotrophic effects of apolipoprotein E in aged transgenic mice. Neurosci. Lett. 265, 218–222.

    PubMed  CAS  Google Scholar 

  • Weisgraber K. H. (2001) Apolipoprotein E: Structure-function relationships. Adv. Protein Chem. 45, 249–302.

    Article  Google Scholar 

  • White F., Nicoll J. A., Roses A. D., and Horsburgh K. (2001) Impaired neuronal plasticity in transgenic mice expressing human apolipoprotein E4 compared to E3 in a model of entorhinal cortex lesion. Neurobiol. Dis. 8, 611–625.

    PubMed  CAS  Google Scholar 

  • Wolozin B., Kellman W., Ruosseau P., Celesia G. G., and Siegel G. (2000) Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch. Neurol. 57, 1439–1443.

    PubMed  CAS  Google Scholar 

  • Woolley C. S. and McEwen B. S. (1993) Roles of estradiol and progesterone in regulation of hippocampal dendritic spine density during the estrous cycle in the rat. J. Comp. Neurol. 336, 293–306.

    PubMed  CAS  Google Scholar 

  • Yaffe K., Barrett-Connor E., Lin F., and Grady D. (2002) Serum lipoprotein levels, statin use, and cognitive function in older women. Arch. Neurol 59, 378–384.

    PubMed  Google Scholar 

  • Yaffe K., Cauley J., Sands L., and Browner W. (1997) Apolipoprotein E phenotype and cognitive decline in a prospective study of elderly community women. Arch. Neurol. 54, 1110–1114.

    PubMed  CAS  Google Scholar 

  • Yaffe K., Haan M., Byers A., and Tangen C. (2000) Estrogen use, APOE, and cognitive decline—evidence of gene-environment interaction. Neurology 54, 1949–1953.

    PubMed  CAS  Google Scholar 

  • Zubenko G. S., Kopp U., Seto T., and Firestone L. L. (1999) Platelet membrane fluidity individuals at risk for Alzheimer’s disease: a comparison of results from fluorescence spectroscopy and electron spin resonance spectroscopy. Psychopharmacology (Berl.) 145, 175–180.

    CAS  Google Scholar 

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    Bruce Teter

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Teter, B. ApoE-dependent plasticity in Alzheimer’s disease. J Mol Neurosci 23, 167–179 (2004). https://doi.org/10.1385/JMN:23:3:167

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