Evidence for normal aging of the septo-hippocampal cholinergic system in apoE (−/−) mice but impaired clearance of axonal degeneration products following injury
Abstract
The association of the epsilon4 allele of apoE with increased risk for Alzheimer's disease (AD) and with poor clinical outcome after certain acute brain injuries has sparked interest in the neurobiology of apoE. ApoE (-/-) mice provide a tool to investigate the role of apoE in the nervous system in vivo. Since integrity of the basal forebrain cholinergic system is severely compromised in AD, with severity of dysfunction correlating with apoE4 gene dosage, the present study tested the hypothesis that apoE is required to maintain the normal integrity of basal forebrain cholinergic neurons (BFCNs). Histological and biochemical analyses of the septo-hippocampal cholinergic system were performed in apoE (-/-) mice during aging and following injury. Using unbiased quantitative methods, there was little or no evidence for defects in the septo-hippocampal cholinergic system, as assessed by p75(NTR)-immunoreactive neuron number and size in the medial septum, cholinergic fiber density in the hippocampus, and choline acetyltransferase activity in the hippocampus, cortex, and striatum in aged apoE (-/-) mice (up to 24 months of age) as compared to age-matched wild-type mice of the same strain. In addition, cholinergic neuronal survival and size following fimbria-fornix transection in apoE (-/-) mice did not differ from controls. However, following entorhinal cortex lesion, there was persistence of degeneration products in the deafferented hippocampus in apoE (-/-) mice. These data sugges…
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Whether apoE-containing lipoproteins play a major role in supporting synaptogenesis and maintenance of synaptic connections in vivo in the uninjured brain has not yet been proven.
“Whether apoE-containing lipoproteins play a major role in supporting synaptogenesis and maintenance of synaptic connections in vivo in the uninjured brain has not yet been proven, as several studies have shown that the brain of apoE knock-out mice for the most part appears normal in the absence of injury (Anderson et al., 1998; Fagan et al., 1998).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Fagan et al., 1998
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Plump, A. S., Smith, J. D., Hayek, T., Aalto-Setälä, K., Walsh, A., Verstuyft, J. G., Rubin, E. M., & Breslow, J. L. (1992) · Cell · doi:10.1016/0092-8674(92)90362-g · Cited by 2,263 · see citing works
Lack of apolipoprotein E dramatically reduces amyloid β-peptide deposition
Bales, K. R., Verina, T., Dodel, R. C., Du, Y., Altstiel, L., Bender, M., Hyslop, P., Johnstone, E. M., Little, S. P., Cummins, D. J., et al. (1997) · Nature Genetics · doi:10.1038/ng1197-263 · Cited by 830 · see citing works
Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins
Pitas, R. E., Boyles, J. K., Lee, S. H., Foss, D., & Mahley, R. W. (1987) · Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism · doi:10.1016/0005-2760(87)90295-5 · Cited by 693 · see citing works
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The role of apolipoprotein E in Alzheimer's disease
Kim, J., Basak, J. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.06.026 · Cited by 1,661 · see citing works
Self-citationApolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease
Holtzman, D. M., Herz, J., & Bu, G. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006312 · Cited by 782 · see citing works
Self-citationHoltzman, D. M., Bales, K. R., Wu, S., Bhat, P., Parsadanian, M., Fagan, A. M., Chang, L. K., Sun, Y., & Paul, S. M. (1999) · Journal of Clinical Investigation · doi:10.1172/jci6179 · Cited by 349 · see citing works
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Riddell, D. R., Zhou, H., Atchison, K., Warwick, H. K., Atkinson, P. J., Jefferson, J., Xu, L., Aschmies, S., Kirksey, Y., Hu, Y., et al. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.1972-08.2008 · Cited by 342 · see citing works
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Malik, M., Parikh, I., Vasquez, J. B., Smith, C., Tai, L., Bu, G., LaDu, M. J., Fardo, D. W., Rebeck, G. W., & Estus, S. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0048-1 · Cited by 161 · see citing works
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Hartman, R. E., Laurer, H., Longhi, L., Bales, K. R., Paul, S. M., McIntosh, T. K., & Holtzman, D. M. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-23-10083.2002 · Cited by 115 · see citing works
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- Authors
- Fagan, A. M., Murphy, B. A., Patel, S. N., Kilbridge, J. F., Mobley, W. C., Bu, G., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- University of California, San Francisco (US)
- Corresponding author
- Fagan, Anne M.
- Venue
- Experimental Neurology
- Publisher
- Elsevier BV
- Published
- 1998-06
- Volume
- 151
- Issue
- 2
- Pages
- 314-325
- ISSN
- 0014-4886 (ISSN-L)
- OpenAlex
- W2015859225
- Cited by
- 116
- References
- 3
- Citations by year
- 2025: 1 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 2 · 2018: 1 · 2017: 5 · 2016: 3 · 2015: 1 · 2014: 2 · 2013: 2 · 2012: 5
- FWCI
- 7.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- University of California, San Francisco
- National Institute on Aging (AG08939, AG 05681, P50AG005681, AG13956)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- apolipoprotein E, ApoE-deficient mice, basal forebrain cholinergic neurons, normal aging, Alzheimer's disease, axonal degeneration, entorhinal cortex lesion, fimbria-fornix transection, choline acetyltransferase, p75 neurotrophin receptor, brain injury
- MeSH terms
- Aging, Animals, Apolipoproteins E, Cell Survival, Choline O-Acetyltransferase, Cholinergic Fibers, Genotype, Male, Mice, Inbred C57BL, Mice, Mutant Strains, Nerve Degeneration, Septal Nuclei, Entorhinal Cortex, Dentate Gyrus, Axotomy, Mice
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