Summary
Apolipoprotein E (apoE) is a 34000-Da protein that functions in the redistri bution of lipids among various tissues. Several observations over the years have suggested that apoE has a role in neurobiology. Most recently it has been associated with the pathogenesis of Alzheimer’s disease. One possible mechanism of apoE involvement in this disease may be modulation of the cytoskeleton in neurons and alteration of neurite extension and branching.
Our studies showed that isoforms of apoE exert differential effects on neuronal growth (i.e., neurite extension and branching) in vitro. When combined with a source of lipid, apoE3 stimulated neurite extension in peripheral nervous system neurons (dorsal root ganglia), whereas apoE4 inhibited it. Similar results were obtained with central nervous system neurons (murine neuroblastoma Neuro-2a cells). On the other hand, addition of free apoE3 or apoE4 without lipid to the dorsal root ganglion or Neuro-2a cells had no effect on neurite outgrowth. The apoE4-mediated effects on inhibition of neurite extension require lipoprotein receptor binding and internalization to elicit the response, and the receptor responsible for the apoE4 effect has been identified as the low density lipoprotein (LDL) receptor-related protein.
Recently, studies have been undertaken to determine the effect of apoE on the microtubules of neurons. When neurons were incubated with apoE3 plus a source of lipid, the microtubules were well-formed and extended throughout the cells. On the other hand, neurons incubated with apoE4 plus a source of lipid displayed widely dispersed tubulin and very few well-formed microtubules. Quantitation of monomeric and polymeric tubulin revealed that the tubulin in the apoE4-treated cells was primarily monomeric.
ApoE may impact the stability of microtubules in an isoform-specifìc manner and affect synaptic remodeling, possibly accounting for the association of the apoE4 isoform with Alzheimer’s disease.
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References
Bellosta S, Nathan BP, Orth M, Dong L-M, Mahley RW, Pitas RE (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
Boyles JK, Pitas RE, Wilson E, Mahley RW, Taylor JM (1985) Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system. J Clin Invest 76: 1501–1513
Boyles JK, Zoellner CD, Anderson LJ, Kosik LM, Pitas RE, Weisgraber KH, Hui DY, Mahley RW, Gebicke-Haerter PJ, Ignatius MJ, Shooter EM (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
Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261: 921–923
Crowther RA (1993) Tau protein and paired helical filaments of Alzheimer’s disease. Curr Opin Struct Biol 3: 202–206
Elshourbagy NA, Liao WS, Mahley RW, Taylor JM (1985) Apolipoprotein E mRNA is abundant in the brain and adrenals, as well as in the liver, and is present in other peripheral tissues of rats and marmosets. Proc Natl Acad Sci USA 82: 203–207
Handelmann GE, Boyles JK, Weisgraber KH, Mahley RW, Pitas RE (1992) Effects of apolipoprotein E, ß-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
Ignatius MJ, Gebicke-Härter PJ, Skene JHP, Schilling JW, Weisgraber KH, Mahley RW, Shooter EM (1986) Expression of apolipoprotein E during nerve degeneration and regeneration. Proc Natl Acad Sci USA 83: 1125–1129
Ignatius MJ, Shooter EM, Pitas RE, Mahley RW (1987) Lipoprotein uptake by neuronal growth cones in vitro. Science 236: 959–962
Mahley RW (1988) Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 240: 622–630
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA work group under the auspices of department of health and human services task force on Alzheimer’s disease. Neurology 34: 939–944
Müller HW, Gebicke-Härter PJ, Hangen DH, Shooter EM (1985) A specific 37 000-dalton protein that accumulates in regenerating but not in nonregenerating mammalian nerves. Science 228: 499–501
Nathan BP, Bellosta S, Sanan DA, Weisgraber KH, Mahley RW, Pitas RE (1994a) Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro. Science 264: 850–852
Nathan BP, Bellosta S, Mahley RW, Pitas RE (1994b) Apolipoprotein E3-and E4-induced differences in neurite outgrowth are associated with differences in the subcellular localiza tion of apolipoprotein E. Society for Neuroscience 20 (Part 2): 1033 (Abstr.)
Nathan BP, Chang K-C, Bellosta S, Brisch E, Ge N, Mahley RW, Pitas RE (1995a) The inhibitory effect of apolipoprotein E4 on neurite outgrowth is associated with microtubule depolymerization. J Biol Chem 270: 19791–19799
Nathan BP, Chang K-C, Bellosta S, Mahley RW, Pitas RE (1995b) The inhibition of neurite outgrowth by apolipoprotein E4 is mediated through the low density lipoprotein receptorrelated protein. Society for Neuroscience 21 (Part 2): 1009 (abstract)
Pitas RE, Boyles JK, Lee SH, Foss D, Mahley RW (1987a) Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins. Biochim Biophys Acta 917:148–161
Pitas RE, Boyles JK, Lee SH, Hui DY, Weisgraber KH (1987b) Lipoproteins and their receptors in the central nervous system: characterization of the lipoproteins in cerebrospinal fluid and identification of apolipoprotein B,E(LDL) receptors in the brain. J Biol Chem 262: 14352–14360
Roses AD (1994) The Alzheimer diseases. Curr Neurol 14: 111–141
Saunders AM, Strittmatter WJ, Schmechel D, St George-Hyslop PH, Pericak-Vance MA, Joo SH, Rosi BL, Gusella JF, Crapper-MacLachlan DR, Alberts MJ, Hulette C, Crain B, Goldgaber D, Roses AD (1993) Association of apolipoprotein E allele ε4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43: 1467–1472
Selkoe DJ (1991) The molecular pathology of Alzheimer’s disease. Neuron 6: 487–198
Strittmatter WJ, Weisgraber KH, Goedert M, Saunders AM, Huang D, Corder EH, Dong L-M, Jakes R, Alberts MJ, Gilbert JR, Han S-H, Hulette C, Einstein G, Schmechel DE, Pericak Vance MA, Roses AD (1994) Hypothesis: microtubule instability and paired helical filament formation in the Alzheimer disease brain are related to apolipoprotein E genotype. Exp Neurol 125: 163–171
Weisgraber KH, Roses AD, Strittmatter WJ (1994a) The role of apolipoprotein E in the nervous system. Curr Opin Lipidol 5: 110–116
Weisgraber KH, Pitas RE, Mahley RW (1994b) Lipoproteins, neurobiology, and Alzheimer’s disease: structure and function of apolipoprotein E. Curr Opin Struct Biol 4: 507–515
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© 1996 Springer-Verlag Berlin Heidelberg
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Mahley, R.W., Nathan, B.P., Bellosta, S., Pitas, R.E. (1996). Apolipoprotein E: Structure, Function, and Possible Roles in Modulating Neurite Extension and Cytoskeletal Activity. In: Roses, A.D., Weisgraber, K., Christen, Y. (eds) Apolipoprotein E and Alzheimer’s Disease. Research and Perspectives in Alzheimer’s Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-80109-9_5
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DOI: https://doi.org/10.1007/978-3-642-80109-9_5
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