Apolipoprotein E4 (apoE4) is the most prevalent genetic risk factor for Alzheimer's disease. We utilized apoE4-targeted replacement mice (approved by the Tel Aviv University Animal Care Committee) to investigate whether cholinergic dysfunction, which increases during aging and is a hallmark of Alzheimer's disease, is accentuated by apoE4. This revealed that levels of the pre-synaptic cholinergic marker, vesicular acetylcholine transporter in the hippocampus and the corresponding electrically evoked release of acetylcholine, are similar in 4-month-old apoE4 and apolipoprotein E3 (apoE3) mice. Both parameters decrease with age. This decrease is, however, significantly more pronounced in the apoE4 mice. The levels of cholinacetyltransferase (ChAT), acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) were similar in the hippocampus of young apoE4 and apoE3 mice and decreased during aging. For ChAT, this decrease was similar in the apoE4 and apoE3 mice, whereas it was more pronounced in the apoE4 mice, regarding their corresponding AChE and BuChE levels. The level of muscarinic receptors was higher in the apoE4 than in the apoE3 mice at 4 months and increased to similar levels with age. However, the relative representation of the M1 receptor subtype decreased during aging in apoE4 mice. These results demonstrate impairment of the evoked release of acetylcholine in hippocampus by apoE4 in 12-month-old mice but not in 4-month-old mice. The levels of ChAT and the extent of the M2 receptor-mediated autoregulation of ACh release were similar in the adult mice, suggesting that the apoE4-related inhibition of hippocampal ACh release in these mice is not driven by these parameters. Evoked ACh release from hippocampal and cortical slices is similar in 4-month-old apoE4 and apoE3 mice but is specifically and significantly reduced in hippocampus, but not cortex, of 12-month-old apoE4 mice. This effect is accompanied by decreased VAChT levels. These findings show that the hipocampal cholinergic nerve terminals are specifically affected by apoE4 and that this effect is age dependent.

Department of Neurobiology Sagol School of Neurosciences The George S Wise Faculty of Life Sciences Tel Aviv University Tel Aviv Israel

Department of Neurochemistry Institute of Physiology CAS Vídeňská Czech Republic

Zobrazit více v PubMed

Belinson H. and Michaelson D. M. (2009) Pathological synergism between amyloid‐beta and apolipoprotein E4–the most prevalent yet understudied genetic risk factor for Alzheimer's disease. J. Alzheimers Dis. 17, 469–481. PubMed

Braga I. L., Silva P. N., Furuya T. K., Santos L. C., Pires B. C., Mazzotti D. R., Bertolucci P. H., Cendoroglo M. S. and Smith M. C. (2015) Effect of APOE and CHRNA7 genotypes on the cognitive response to cholinesterase inhibitor treatment at different stages of Alzheimer's disease. Am. J. Alzheimers Dis. Other Demen. 30, 139–144. PubMed PMC

Bronfman F. C., Tesseur I., Hofker M. H., Havekens L. M. and Van Leuven F. (2000) No evidence for cholinergic problems in apolipoprotein E knockout and apolipoprotein E4 transgenic mice. Neuroscience 97, 411–418. PubMed

Cermak J. M., Holler T., Jackson D. A. and Blusztajn J. K. (1998) Prenatal availability of choline modifies development of the hippocampal cholinergic system. FASEB J. 12, 349–357. PubMed

Chan A., Tchantchou F., Graves V., Rozen R. and Shea T. B. (2008) Dietary and genetic compromise in folate availability reduces acetylcholine, cognitive performance and increases aggression: critical role of S‐adenosyl methionine. J. Nutr. Health Aging 12, 252–261. PubMed

Chapman S., Sabo T., Roses A. D. and Michaelson D. M. (2000) Reversal of presynaptic deficits of apolipoprotein E‐deficient mice in human apolipoprotein E transgenic mice. Neuroscience 97, 419–424. PubMed

Corder E. H., Saunders A. M., Strittmatter W. J., Schmechel D. E., Gaskell P. C., Small G. W., Roses A. D., Haines J. L. and Pericak‐Vance M. A. (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

Craig L. A., Hong N. S. and McDonald R. J. (2011) Revisiting the cholinergic hypothesis in the development of Alzheimer's disease. Neurosci. Biobehav. Rev. 35, 1397–1409. PubMed

Dumanis S. B., DiBattista A. M., Miessau M., Moussa C. E. and Rebeck G. W. (2013) APOE genotype affects the pre‐synaptic compartment of glutamatergic nerve terminals. J. Neurochem. 124, 4–14. PubMed PMC

Erickson J. D., Varoqui H., Schafer M. K., Modi W., Diebler M. F., Weihe E., Rand J., Eiden L. E., Bonner T. I. and Usdin T. B. (1994) Functional identification of a vesicular acetylcholine transporter and its expression from a “cholinergic” gene locus. J. Biol. Chem. 269, 21929–21932. PubMed

Holler T., Berse B., Cermak J. M., Diebler M. F. and Blusztajn J. K. (1996) Differences in the developmental expression of the vesicular acetylcholine transporter and choline acetyltransferase in the rat brain. Neurosci. Lett. 212, 107–110. PubMed

Janickova H., Rudajev V., Zimcik P., Jakubik J., Tanila H., El‐Fakahany E. E. and Dolezal V. (2013) Uncoupling of M1 muscarinic receptor/G‐protein interaction by amyloid beta(1‐42). Neuropharmacology 67, 272–283. PubMed

Lazareno S., Dolezal V., Popham A. and Birdsall N. J. (2004) Thiochrome enhances acetylcholine affinity at muscarinic M4 receptors: receptor subtype selectivity via cooperativity rather than affinity. Mol. Pharmacol. 65, 257–266. PubMed

Liraz O., Boehm‐Cagan A. and Michaelson D. M. (2013) ApoE4 induces Abeta42, tau, and neuronal pathology in the hippocampus of young targeted replacement apoE4 mice. Mol. Neurodegener. 8, 16. PubMed PMC

Machova E., Jakubik J., Michal P., Oksman M., Iivonen H., Tanila H. and Dolezal V. (2008) Impairment of muscarinic transmission in transgenic APPswe/PS1dE9 mice. Neurobiol. Aging 29, 368–378. PubMed

Machova E., Rudajev V., Smyckova H., Koivisto H., Tanila H. and Dolezal V. (2010) Functional cholinergic damage develops with amyloid accumulation in young adult APPswe/PS1dE9 transgenic mice. Neurobiol. Dis. 38, 27–35. PubMed

Okuda T., Haga T., Kanai Y., Endou H., Ishihara T. and Katsura I. (2000) Identification and characterization of the high‐affinity choline transporter. Nat. Neurosci. 3, 120–125. PubMed

Pepeu G. and Giovannelli L. (1994) The central cholinergic system during aging. Prog. Brain Res. 100, 67–71. PubMed

Pomara N., Willoughby L. M., Wesnes K. and Sidtis J. J. (2004) Increased anticholinergic challenge‐induced memory impairment associated with the APOE‐epsilon4 allele in the elderly: a controlled pilot study. Neuropsychopharmacology 29, 403–409. PubMed

Reinvang I., Espeseth T. and Westlye L. T. (2013) APOE‐related biomarker profiles in non‐pathological aging and early phases of Alzheimer's disease. Neurosci. Biobehav. Rev. 37, 1322–1335. PubMed

Saunders A. M., Strittmatter W. J., Schmechel D. et al (1993) Association of apolipoprotein E allele epsilon 4 with late‐onset familial and sporadic Alzheimer's disease. Neurology 43, 1467–1472. PubMed

Schliebs R. and Arendt T. (2011) The cholinergic system in aging and neuronal degeneration. Behav. Brain Res. 221, 555–563. PubMed

Shinoe T., Matsui M., Taketo M. M. and Manabe T. (2005) Modulation of synaptic plasticity by physiological activation of M1 muscarinic acetylcholine receptors in the mouse hippocampus. J. Neurosci. 25, 11194–11200. PubMed PMC

Specht C. G. and Schoepfer R. (2001) Deletion of the alpha‐synuclein locus in a subpopulation of C57BL/6J inbred mice. BMC Neurosci. 2, 11. PubMed PMC

Sullivan P. M., Mezdour H., Aratani Y., Knouff C., Najib J., Reddick R. L., Quarfordt S. H. and Maeda N. (1997) Targeted replacement of the mouse apolipoprotein E gene with the common human APOE3 allele enhances diet‐induced hypercholesterolemia and atherosclerosis. J Biol Chem 272, 17972–17980. PubMed

Sullivan P. M., Han B., Liu F., Mace B. E., Ervin J. F., Wu S., Koger D., Paul S. and Bales K. R. (2011) Reduced levels of human apoE4 protein in an animal model of cognitive impairment. Neurobiol. Aging 32, 791–801. PubMed

Wurtman R. J. (2008) Synapse formation and cognitive brain development: effect of docosahexaenoic acid and other dietary constituents. Metabolism 57(Suppl 2), S6–S10. PubMed PMC

Yun S. H., Park K. A., Sullivan P., Pasternak J. F., Ladu M. J. and Trommer B. L. (2005) Blockade of nicotinic acetylcholine receptors suppresses hippocampal long‐term potentiation in wild‐type but not ApoE4 targeted replacement mice. J. Neurosci. Res. 82, 771–777. PubMed

Cholesterol-dependent amyloid β production: space for multifarious interactions between amyloid precursor protein, secretases, and cholesterol