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Modulation of Alzheimer-like synaptic and cholinergic deficits in transgenic mice by human apolipoprotein E depends on isoform, aging, and overexpression of amyloid β peptides but not on plaque formation
Open accessAbstract
The most frequent human apolipoprotein (apo) E isoforms, E3 and E4, differentially affect Alzheimer's disease (AD) risk (E4 > E3) and age of onset (E4 < E3). Compared with apoE3, apoE4 promotes the cerebral deposition of amyloid beta (Abeta) peptides, which are derived from the amyloid precursor protein (APP) and play a central role in AD. However, it is uncertain whether Abeta deposition into plaques is the main mechanism by which apoE isoforms affect AD. We analyzed murine apoE-deficient transgenic mice expressing in their brains human APP (hAPP) and Abeta together with apoE3 or apoE4. Because cognitive decline in AD correlates better with decreases in synaptophysin-immunoreactive presynaptic terminals, choline acetyltransferase (ChAT) activity, and ChAT-positive fibers than with plaque load, we compared these parameters in hAPP/apoE3 and hAPP/apoE4 mice and singly transgenic controls at 6-7, 12-15, and 19-24 months of age. Brain aging in the context of high levels of nondeposited human Abeta resulted in progressive synaptic/cholinergic deficits. ApoE3 delayed the synaptic deficits until old age, whereas apoE4 was not protective at any of the ages analyzed. Old hAPP/apoE4 mice had more plaques than old hAPP/apoE3 mice, but synaptic/cholinergic deficits preceded plaque formation in hAPP/apoE4 mice. Moreover, despite their different plaque loads, old hAPP/apoE4 and hAPP/apoE3 mice had comparable synaptic/cholinergic deficits, and these deficits were found not only in the hippocampus but also in the neocortex, which in most mice contained no plaques. Thus, apoE3, but not apoE4, delays age- and Abeta-dependent synaptic deficits through a plaque-independent mechanism. This difference could contribute to the differential effects of apoE isoforms on the risk and onset of AD.
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“Introduction of human APOE to existing FAD-Tg mice significantly delays plaque deposition, although once detected, plaque levels are generally greater with APOE4 than APOE3 (3, 6 -8).”
From APOE4-specific Changes in Aβ Accumulation in a New Transgenic Mouse Model of Alzheimer Disease (2012) · cites this paper as [6]
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“ApoE has a major impact on the generation of amyloid deposits in the AD mouse brain and deletion of ApoE in most AD mouse models significantly inhibits amyloid plaque formation [6], [7], [8].”
From Lack of LDL receptor enhances amyloid deposition and decreases glial response in an Alzheimer's disease mouse model (2011) · cites this paper as [6]
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“Other studies using transgenic mice that possess different human apoE transgenes also demonstrate an isoform-specific difference (E4>E3) in Aβ deposition (Buttini et al., 2002; Dolev and Michaelson, 2004).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Buttini et al., 2002
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“APP transgenic mice deficient for ApoE show a dramatic decrease in fibrillary amyloid deposits [5], [6], [7], [8], [9].”
From Lack of LDL receptor enhances amyloid deposition and decreases glial response in an Alzheimer's disease mouse model (2011) · cites this paper as [6]
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Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359
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“Because synaptic deficits correlate well with the development of cognitive deficits in AD (DeKosky and Scheff, 1990; Terry et al., 1991; Langlais et al., 1993; Samuel et al., 1997; Sze et al., 1997; Brown et al., 1998), the differential effects of apoE3 and apoE4 identified here might relate closely to the effects of…”
BackgroundInfluentialAlzheimer's Disease: Genes, Proteins, and Therapy
Selkoe, D. J. (2001) · Physiological Reviews · doi:10.1152/physrev.2001.81.2.741 · Cited by 6,063 · cited 3×
“These associations have widely been interpreted as evidence that apoE4 increases AD risk through its effect on amyloid deposition (Holtzman et al., 2000a,b; Selkoe, 2001).”
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“We focused our analysis on SYN-IR presynaptic terminals, choline acetyltransferase (ChAT) activity, and cholinergic fibers, because decreases in these parameters correlate well with cognitive decline in AD (Terry et al., 1991; Samuel et al., 1997; Sze et al., 1997; Brown et al., 1998).”
BackgroundDiffusible, nonfibrillar ligands derived from Aβ 1–42 are potent central nervous system neurotoxins
Lambert, M. P., Barlow, A. K., Chromy, B. A., Edwards, C., Freed, R., Liosatos, M., Morgan, T. E., Rozovsky, I., Trommer, B., Viola, K. L., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.11.6448 · Cited by 3,506 · cited 1×
“…evidence is mounting that ADrelated synaptic degeneration and functional neuronal impairments may be caused primarily by nondeposited forms of A (Lambert et al., 1998; Hartley et al., 1999; Holcomb et al., 1999; Hsia et al., 1999; Lue et al., 1999; McLean et al., 1999; Mucke et al., 2000; Raber…”
BackgroundAlzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein
Games, D., Adams, D., Alessandrini, R., Barbour, R., Borthelette, P., Blackwell, C., Carr, T., Clemens, J., Donaldson, T., Gillespie, F., et al. (1995) · Nature · doi:10.1038/373523a0 · Cited by 2,516 · cited 2×
“…(Pike et al., 1993; Yankner, 1996; Klein et al., 2001), injected into the brain (Geula et al., 1998), or produced in neurons of transgenic mice (Games et al., 1995; Masliah et al., 1996, 2001; Nalbantoglu et al., 1997; Calhoun et al., 1998; Price et al., 1998; Hsia et al., 1999; Mucke et al.,…”
BackgroundSelf-citationSynapse loss in frontal cortex biopsies in Alzheimer's disease: Correlation with cognitive severity
DeKosky, S. T., & Scheff, S. W. (1990) · Annals of Neurology · doi:10.1002/ana.410270502 · Cited by 2,376 · cited 2×
“Because synaptic deficits correlate well with the development of cognitive deficits in AD ( DeKosky and Scheff, 1990; Terry et al., 1991; Langlais et al., 1993; Samuel et al., 1997; Sze et al., 1997; Brown et al., 1998), the differential effects of apoE3 and apoE4 identified here might relate closely to the effects of…”
BackgroundPerry, E., Tomlinson, B. E., Blessed, G., Bergmann, K., Gibson, P., & Perry, R. H. (1978) · British medical journal · doi:10.1136/bmj.2.6150.1457 · Cited by 2,043 · cited 2×
“Its activity is 40–90% lower in AD brains than in control brains, and this reduction correlates with cognitive decline (Perry et al., 1978; Davies, 1979; Wilcock et al., 1982; Sims et al., 1983; Neary et al., 1986; Bierer et al., 1995; Samuel et al., 1997; Cummings, 2000).”
BackgroundMucke, L., Masliah, E., Yu, G.-Q., Mallory, M., Rockenstein, E. M., Tatsuno, G., Hu, K., Kholodenko, D., Johnson-Wood, K., & McConlogue, L. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-11-04050.2000 · Cited by 1,856 · cited 12×
“…terminals in hAPP mice expressing high levels of soluble human A On the murine apoE wild-type background, hAPP mice develop an age-dependent loss of SYN-IR presynaptic terminals that is associated with major deficits in synaptic transmission strength (Hsia et al., 1999; Mucke et al., 2000).”
BackgroundInfluentialCNS synaptogenesis promoted by glia-derived cholesterol
Mauch, D. H., Nägler, K., Schumacher, S., Göritz, C., Müller, E.-C., Otto, A., & Pfrieger, F. W. (2001) · Science · doi:10.1126/science.294.5545.1354 · Cited by 1,711 · cited 1×
“…and A -dependent synaptic deficits include promotion of neurite extension (Nathan et al., 1994; Holtzman and Fagan, 1998) and synapse formation (Mauch et al., 2001), stabilization of microtubules (Strittmatter et al., 1994; Nathan et al., 1995) and endosomal–lysosomal membranes (Ji et al.,…”
BackgroundSoluble Amyloid β Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease
Lue, L.-F., Kuo, Y.-M., Roher, A. E., Brachova, L., Shen, Y., Sue, L., Beach, T., Kurth, J. H., Rydel, R. E., & Rogers, J. (1999) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)65184-x · Cited by 1,530 · cited 3×
“…and in hAPP transgenic mice have demonstrated that AD-related synaptic and functional neuronal deficits correlate better with levels of nondeposited A than with plaque load (Holcomb et al., 1999; Hsia et al., 1999; Lue et al., 1999; McLean et al., 1999; Mucke et al., 2000; Raber et al., 2000).”
BackgroundSchmechel, D. E., Saunders, A. M., Strittmatter, W. J., Crain, B. J., Hulette, C. M., Joo, S. H., Pericak-Vance, M. A., Goldgaber, D., & Roses, A. D. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.20.9649 · Cited by 1,525 · cited 1×
“The two most frequent isoforms differ not only in their effects on A deposition (E4 E3) (Rebeck et al., 1993; Schmechel et al., 1993; Berr et al., 1994; Heinonen et al., 1995; Hyman et al., 1995; Gearing et al., 1996; Ishii et al., 1997; Johnson et al., 1998; McNamara et al., 1998; Holtzman et al.,…”
BackgroundNeurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state
Pike, C., Burdick, D., Walencewicz, A., Glabe, C., & Cotman, C. (1993) · The Journal of Neuroscience · doi:10.1523/jneurosci.13-04-01676.1993 · Cited by 1,417 · cited 1×
“Human A is neurotoxic when added to cultures of neural cells or tissue sections (Pike et al., 1993; Yankner, 1996; Klein et al., 2001), injected into the brain (Geula et al., 1998), or produced in neurons of transgenic mice (Games et al., 1995; Masliah et al., 1996, 2001; Nalbantoglu et al., 1997;…”
BackgroundPatterns of Brain Activation in People at Risk for Alzheimer's Disease
Bookheimer, S. Y., Strojwas, M. H., Cohen, M. S., Saunders, A. M., Pericak-Vance, M. A., Mazziotta, J. C., & Small, G. W. (2000) · New England Journal of Medicine · doi:10.1056/nejm200008173430701 · Cited by 1,328 · cited 5×
“…to have relatively little impact on the severity and progression of neuronal deficits in old age and during later stages of AD (Farrer et al., 1997; Bookheimer et al., 2000; Greenwood et al., 2000; Small et al., 2000; Yaffe et al., 2000; Caselli et al., 2001; Chapman et al., 2001; Reiman et al.,…”
BackgroundInfluentialCorrelation Between Elevated Levels of Amyloid β-Peptide in the Brain and Cognitive Decline
Näslund, J. (2000) · JAMA · doi:10.1001/jama.283.12.1571 · Cited by 1,268 · cited 1×
“…is responsible for the dysfunction and degeneration of neurons in AD remains a matter of active study and debate (Terry, 1996; Davis and Chisholm, 1997; Hartley et al., 1999; Hsia et al., 1999; Lue et al., 1999; McLean et al., 1999; Mucke et al., 2000; Näslund et al., 2000; Klein et al., 2001).”
BackgroundPlaque-independent disruption of neural circuits in Alzheimer’s disease mouse models
Hsia, A. Y., Masliah, E., McConlogue, L., Yu, G.-Q., Tatsuno, G., Hu, K., Kholodenko, D., Malenka, R. C., Nicoll, R. A., & Mucke, L. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.6.3228 · Cited by 1,123 · cited 17×
“…terminals in hAPP mice expressing high levels of soluble human A On the murine apoE wild-type background, hAPP mice develop an age-dependent loss of SYN-IR presynaptic terminals that is associated with major deficits in synaptic transmission strength (Hsia et al., 1999; Mucke et al., 2000).”
BackgroundResultInfluentialSelf-citationApolipoprotein E in sporadic Alzheimer's disease: Allelic variation and receptor interactions
William Rebeck, G., Reiter, J. S., Strickland, D. K., & Hyman, B. T. (1993) · Neuron · doi:10.1016/0896-6273(93)90070-8 · Cited by 1,107 · cited 1×
“The two most frequent isoforms differ not only in their effects on A deposition (E4 E3) (Rebeck et al., 1993; Schmechel et al., 1993; Berr et al., 1994; Heinonen et al., 1995; Hyman et al., 1995; Gearing et al., 1996; Ishii et al., 1997; Johnson et al., 1998; McNamara et al., 1998; Holtzman et al.,…”
BackgroundTargeting small Aβ oligomers: the solution to an Alzheimer's disease conundrum?
Klein, W. (2001) · Trends in Neurosciences · doi:10.1016/s0166-2236(00)01749-5 · Cited by 989 · cited 4×
“Human A is neurotoxic when added to cultures of neural cells or tissue sections (Pike et al., 1993; Yankner, 1996; Klein et al., 2001), injected into the brain (Geula et al., 1998), or produced in neurons of transgenic mice (Games et al., 1995; Masliah et al., 1996, 2001; Nalbantoglu et al., 1997;…”
BackgroundInfluentialMechanisms of Neuronal Degeneration in Alzheimer's Disease
Yankner, B. A. (1996) · Neuron · doi:10.1016/s0896-6273(00)80115-4 · Cited by 953 · cited 1×
“Human A is neurotoxic when added to cultures of neural cells or tissue sections (Pike et al., 1993; Yankner, 1996; Klein et al., 2001), injected into the brain (Geula et al., 1998), or produced in neurons of transgenic mice (Games et al., 1995; Masliah et al., 1996, 2001; Nalbantoglu et al., 1997;…”
BackgroundHoltzman, D. M., Bales, K. R., Tenkova, T., Fagan, A. M., Parsadanian, M., Sartorius, L. J., Mackey, B., Olney, J., McKeel, D., Wozniak, D., et al. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.050004797 · Cited by 937 · cited 6×
“…Berr et al., 1994; Heinonen et al., 1995; Hyman et al., 1995; Gearing et al., 1996; Ishii et al., 1997; Johnson et al., 1998; McNamara et al., 1998; Holtzman et al., 2000a,b) but also in their capacity to protect the brain against diverse injuries, including those elicited by excitotoxins,…”
BackgroundInfluentialBoyles, J. K., Pitas, R. E., Wilson, E., Mahley, R. W., & Taylor, J. M. (1985) · Journal of Clinical Investigation · doi:10.1172/jci112130 · Cited by 829 · cited 1×
“It is expressed at high levels in the brain and can be produced by diverse cell types, including neurons, astrocytes, and microglia (Boyles et al., 1985; Stone et al., 1997; Buttini et al., 1999; Xu et al., 1999, 2000; Dekroon and Armati, 2001).”
BackgroundHartley, D. M., Walsh, D. M., Ye, C. P., Diehl, T., Vasquez, S., Vassilev, P. M., Teplow, D. B., & Selkoe, D. J. (1999) · The Journal of Neuroscience · doi:10.1523/jneurosci.19-20-08876.1999 · Cited by 817 · cited 2×
“…is responsible for the dysfunction and degeneration of neurons in AD remains a matter of active study and debate (Terry, 1996; Davis and Chisholm, 1997; Hartley et al., 1999; Hsia et al., 1999; Lue et al., 1999; McLean et al., 1999; Mucke et al., 2000; Näslund et al., 2000; Klein et al., 2001).”
BackgroundApolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid
Wisniewski, T., & Frangione, B. (1992) · Neuroscience Letters · doi:10.1016/0304-3940(92)90444-c · Cited by 802 · cited 1×
“This finding may be consistent with the notion that the formation of neurotoxic A species depends on the association of A with “pathological molecular chaperones,” such as apoE and apoJ (Wisniewski and Frangione, 1992; Oda et al., 1995; Ma et al., 1996; Permanne et al., 1997).”
ResultDifferential Effects of Apolipoproteins E3 and E4 on Neuronal Growth in Vitro
Nathan, B. P., Bellosta, S., Sanan, D. A., Weisgraber, K. H., Mahley, R. W., & Pitas, R. E. (1994) · Science · doi:10.1126/science.8171342 · Cited by 795 · cited 2×
“Neuroprotective activities of apoE3 that might allow it to delay age- and A -dependent synaptic deficits include promotion of neurite extension (Nathan et al., 1994; Holtzman and Fagan, 1998) and synapse formation (Mauch et al., 2001), stabilization of microtubules (Strittmatter et al., 1994;…”
BackgroundCerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer’s disease
Small, G. W., Ercoli, L. M., Silverman, D. H. S., Huang, S.-C., Komo, S., Bookheimer, S. Y., Lavretsky, H., Miller, K., Siddarth, P., Rasgon, N. L., et al. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.090106797 · Cited by 790 · cited 5×
“…4 alleles but without overt AD revealed decreased brain activity, decreased visual attention, and subtle memory impairments in 4 carriers compared with people with other APOE alleles (Caselli et al., 1999; Bookheimer et al., 2000; Greenwood et al., 2000; Small et al., 2000; Reiman et al., 2001).”
BackgroundInfluentialMiyata, M., & Smith, J. D. (1996) · Nature Genetics · doi:10.1038/ng0996-55 · Cited by 735 · cited 1×
“…extension (Nathan et al., 1994; Holtzman and Fagan, 1998) and synapse formation (Mauch et al., 2001), stabilization of microtubules (Strittmatter et al., 1994; Nathan et al., 1995) and endosomal–lysosomal membranes (Ji et al., 2002), and protection against oxidative stress (Miyata and Smith, 1996).”
BackgroundNeurotransmitter-related enzymes in senile dementia of the alzheimer type
Davies, P. (1979) · Brain Research · doi:10.1016/0006-8993(79)90336-6 · Cited by 634 · cited 2×
“Its activity is 40 –90% lower in AD brains than in control brains, and this reduction correlates with cognitive decline (Perry et al., 1978; Davies, 1979; Wilcock et al., 1982; Sims et al., 1983; Neary et al., 1986; Bierer et al., 1995; Samuel et al., 1997; Cummings, 2000).”
BackgroundMasliah, E., Rockenstein, E., Veinbergs, I., Sagara, Y., Mallory, M., Hashimoto, M., & Mucke, L. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.211412398 · Cited by 607 · cited 2×
“In the presence of murine apoE (Hsia et al., 1999; Mucke et al., 2000; Masliah et al., 2001) or human apoE (this study), A clearly did affect the integrity or function of presynaptic terminals and cholinergic neurons.”
BackgroundSelf-citationPoirier, J., Delisle, M.-C., Quirion, R., Aubert, I., Farlow, M. R., Lahiri, D. K., Hui, S. L., Bertrand, P., Nalbantoglu, J. N., & Gilfix, B. M. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.26.12260 · Cited by 593 · cited 2×
“However, biochemical and neuropathological alterations of the cholinergic system have been detected primarily in later stages of the disease, and their modification by apoE isoforms remains controversial (Poirier et al., 1995; Soininen et al., 1995; Allen et al., 1997; Arendt et al., 1997; Salehi et al., 1998; Gilmor…”
BackgroundBierer, L. M., Haroutunian, V. H., Gabriel, S., Knott, P. J., Carlin, L. S., Purohit, D. P., Perl, D. P., Schmeidler, J., Kanof, P. D., & Davis, K. L. (1995) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1995.64020749.x · Cited by 580 · cited 1×
“Its activity is 40–90% lower in AD brains than in control brains, and this reduction correlates with cognitive decline (Perry et al., 1978; Davies, 1979; Wilcock et al., 1982; Sims et al., 1983; Neary et al., 1986; Bierer et al., 1995; Samuel et al., 1997; Cummings, 2000).”
BackgroundSZE, C.-I., TRONCOSO, J. C., KAWAS, C., MOUTION, P., PRICE, D. L., & MARTIN, L. J. (1997) · Journal of Neuropathology and Experimental Neurology · doi:10.1097/00005072-199708000-00011 · Cited by 562 · cited 2×
“We focused our analysis on SYN-IR presynaptic terminals, choline acetyltransferase (ChAT) activity, and cholinergic fibers, because decreases in these parameters correlate well with cognitive decline in AD (Terry et al., 1991; Samuel et al., 1997; Sze et al., 1997; Brown et al., 1998).”
BackgroundWilcock, G. K., Esiri, M. M., Bowen, D. M., & Smith, C. C. T. (1982) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(82)90045-4 · Cited by 553 · cited 1×
“Its activity is 40–90% lower in AD brains than in control brains, and this reduction correlates with cognitive decline (Perry et al., 1978; Davies, 1979; Wilcock et al., 1982; Sims et al., 1983; Neary et al., 1986; Bierer et al., 1995; Samuel et al., 1997; Cummings, 2000).”
Background(1997) · doi:10.1073/pnas.94.4.1550 · Cited by 535 · cited 1×
“Frozen brain tissues were homogenized in guanidine buffer, and human A peptides were quantitated by ELISA as described previously (Johnson-Wood et al., 1997).”
MethodAging renders the brain vulnerable to amyloid β-protein neurotoxicity
Guela, C., Wu, C.-K., Saroff, D., Lorenzo, A., Yuan, M., & Yankner, B. A. (1998) · Nature Medicine · doi:10.1038/nm0798-827 · Cited by 520 · cited 1×
“…when added to cultures of neural cells or tissue sections (Pike et al., 1993; Yankner, 1996; Klein et al., 2001), injected into the brain (Geula et al., 1998), or produced in neurons of transgenic mice (Games et al., 1995; Masliah et al., 1996, 2001; Nalbantoglu et al., 1997; Calhoun et…”
BackgroundNeuron loss in APP transgenic mice
Calhoun, M. E., Wiederhold, K.-H., Abramowski, D., Phinney, A. L., Probst, A., Sturchler-Pierrat, C., Staufenbiel, M., Sommer, B., & Jucker, M. (1998) · Nature · doi:10.1038/27351 · Cited by 502 · cited 2×
“…et al., 1993; Yankner, 1996; Klein et al., 2001), injected into the brain (Geula et al., 1998), or produced in neurons of transgenic mice (Games et al., 1995; Masliah et al., 1996, 2001; Nalbantoglu et al., 1997; Calhoun et al., 1998; Price et al., 1998; Hsia et al., 1999; Mucke et al., 2000).”
BackgroundReiman, E. M., Caselli, R. J., Chen, K., Alexander, G. E., Bandy, D., & Frost, J. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.061509598 · Cited by 467 · cited 3×
“…effects of apoE3 and apoE4 on the development of AD manifestations were apparent primarily during early but not late stages of the aging process (Farrer et al., 1997; Bookheimer et al., 2000; Greenwood et al., 2000; Small et al., 2000; Yaffe et al., 2000; Chapman et al., 2001; Reiman et al., 2001).”
BackgroundStrittmatter, W. J., Weisgraber, K. H., Goedert, M., Saunders, A. M., Huang, D., Corder, E. H., Dong, L., Jakes, R., Alberts, M. J., Gilbert, J. R., et al. (1994) · Experimental Neurology · doi:10.1006/exnr.1994.1019 · Cited by 433 · cited 1×
“…of neurite extension (Nathan et al., 1994; Holtzman and Fagan, 1998) and synapse formation (Mauch et al., 2001), stabilization of microtubules (Strittmatter et al., 1994; Nathan et al., 1995) and endosomal–lysosomal membranes (Ji et al., 2002), and protection against oxidative stress (Miyata…”
BackgroundPresynaptic Cholinergic Dysfunction in Patients with Dementia
Sims, N. R., Bowen, D. M., Allen, S. J., Smith, C., Neary, D., Thomas, D. J., & DAVISON, A. N. (1983) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1983.tb11311.x · Cited by 421 · cited 1×
“Its activity is 40–90% lower in AD brains than in control brains, and this reduction correlates with cognitive decline (Perry et al., 1978; Davies, 1979; Wilcock et al., 1982; Sims et al., 1983; Neary et al., 1986; Bierer et al., 1995; Samuel et al., 1997; Cummings, 2000).”
BackgroundNeurodegeneration in the Central Nervous System of apoE-Deficient Mice
Masliah, E., Mallory, M. E., Ge, N., Alford, M. F., Veinbergs, I., & Roses, A. D. (1995) · Experimental Neurology · doi:10.1006/exnr.1995.1088 · Cited by 402 · cited 5×
“2) (Masliah et al., 1995b; Buttini et al., 1999, 2000; Hsia et al., 1999; Mucke et al., 2000).”
BackgroundInfluentialHuang, Y., Liu, X. Q., Wyss-Coray, T., Brecht, W. J., Sanan, D. A., & Mahley, R. W. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.151254698 · Cited by 392 · cited 3×
“ApoE levels in brain tissues were quantitated by Western blot analysis as described previously (Huang et al., 1996, 2001).”
BackgroundMethodMasliah, E., Sisk, A., Mallory, M. E., Mucke, L., Schenk, D., & Games, D. (1996) · Journal of Neuroscience · doi:10.1523/jneurosci.16-18-05795.1996 · Cited by 389 · cited 1×
“…et al., 1993; Yankner, 1996; Klein et al., 2001), injected into the brain (Geula et al., 1998), or produced in neurons of transgenic mice (Games et al., 1995; Masliah et al., 1996, 2001; Nalbantoglu et al., 1997; Calhoun et al., 1998; Price et al., 1998; Hsia et al., 1999; Mucke et al., 2000).”
BackgroundCholinesterase Inhibitors: A New Class of Psychotropic Compounds
Cummings, J. L. (2000) · American Journal of Psychiatry · doi:10.1176/ajp.157.1.4 · Cited by 386 · cited 4×
“The therapeutic effect of acetylcholinesterase inhibitors during early stages of AD suggests an early impairment of cholinergic functions (Cummings, 2000; Nakano et al., 2001), and there is evidence that the responsiveness to these compounds is influenced by apoE genotype (Farlow et al.”
BackgroundInfluentialEstrogen use, APOE, and cognitive decline: Evidence of gene–environment interaction
Yaffe, K., Haan, M., Byers, A., Tangen, C., & Kuller, L. (2000) · Neurology · doi:10.1212/wnl.54.10.1949 · Cited by 371 · cited 3×
“As in our mouse models, the differential effects of apoE3 and apoE4 on the development of AD manifestations were apparent primarily during early but not late stages of the aging process (Farrer et al., 1997; Bookheimer et al., 2000; Greenwood et al., 2000; Small et al., 2000; Yaffe et al., 2000; Chapman et al., 2001;…”
BackgroundRaber, J., Wong, D., Buttini, M., Orth, M., Bellosta, S., Pitas, R. E., Mahley, R. W., & Mucke, L. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.18.10914 · Cited by 364 · cited 5×
“ApoE3 and apoE4 singly transgenic mice show similar levels and distributions of human apoE in the brain (Raber et al., 1998; Buttini et al., 1999), and 6-month-old hAPP/apoE3 and hAPP/apoE4 mice have comparable levels of A 1–42 and A 1–x (approximates total A ) in the hippocampus (Raber et al.,…”
BackgroundInfluentialSelf-citationButtini, M., Orth, M., Bellosta, S., Akeefe, H., Pitas, R. E., Wyss‐Coray, T., Mucke, L., & Mahley, R. W. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-12-04867.1999 · Cited by 363 · cited 15×
“The specificity of this immunostain has been documented previously (Buttini et al., 1999).”
BackgroundMethodInfluentialHolcomb, L. A., Gordon, M. N., Jantzen, P., Hsiao, K., Duff, K., & Morgan, D. (1999) · Behavior Genetics · doi:10.1023/a:1021691918517 · Cited by 353 · cited 3×
“Studies in human AD cases and in hAPP transgenic mice have demonstrated that AD-related synaptic and functional neuronal deficits correlate better with levels of nondeposited A than with plaque load (Holcomb et al., 1999; Hsia et al., 1999; Lue et al., 1999; McLean et al., 1999; Mucke et al., 2000; Raber et al., 2000).”
BackgroundOda, T., Wals, P., Osterburg, H. H., Johnson, S. A., Pasinetti, G. M., Morgan, T. E., Rozovsky, I., Stine, W. B., Snyder, S. W., Holzman, T. F., et al. (1995) · Experimental Neurology · doi:10.1006/exnr.1995.1080 · Cited by 352 · cited 1×
“This finding may be consistent with the notion that the formation of neurotoxic A species depends on the association of A with “pathological molecular chaperones,” such as apoE and apoJ (Wisniewski and Frangione, 1992; Oda et al., 1995; Ma et al., 1996; Permanne et al., 1997).”
ResultHoltzman, 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 · cited 1×
“Previous studies of hAPP/apoE transgenic mice focused primarily on amyloid deposition and plaque-related pathology (Holtzman et al., 1999, 2000a,b) but did not examine effects of human apoE isoforms on other AD-related deficits, such as loss of SYN-IR presynaptic terminals, ChAT activity, or…”
BackgroundNalbantoglu, J. N., Santiago, G. T., Lahsaïni, A., Poirier, J., Goncalves, O., Verge, G. M., Momoli, F., Welner, S. A., Massicotte, G., Julien, J., et al. (1997) · Nature · doi:10.1038/387500a0 · Cited by 342 · cited 1×
“…et al., 1993; Yankner, 1996; Klein et al., 2001), injected into the brain (Geula et al., 1998), or produced in neurons of transgenic mice (Games et al., 1995; Masliah et al., 1996, 2001; Nalbantoglu et al., 1997; Calhoun et al., 1998; Price et al., 1998; Hsia et al., 1999; Mucke et al., 2000).”
BackgroundArendt, T., Schindler, C., Brückner, M. K., Eschrich, K., Bigl, V., Zedlick, D., & Marcova, L. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-02-00516.1997 · Cited by 319 · cited 1×
“…of the disease, and their modification by apoE isoforms remains controversial (Poirier et al., 1995; Soininen et al., 1995; Allen et al., 1997; Arendt et al., 1997; Salehi et al., 1998; Gilmor et al., 1999; Bronfman et al., 2000; Corey-Bloom et al., 2000; Tiraboschi et al., 2000; Sjögren et…”
BackgroundHuman Apolipoprotein E4 Domain Interaction
Dong, L.-M., & Weisgraber, K. H. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.32.19053 · Cited by 318
Apolipoprotein E: from atherosclerosis to Alzheimerʼs disease and beyond
Mahley, R. W., & Huang, Y. (1999) · Current Opinion in Lipidology · doi:10.1097/00041433-199906000-00003 · Cited by 308 · cited 2×
“ApoE is a 34 kDa lipid carrier protein that participates in the maintenance and repair of neurons (Mahley and Huang, 1999).”
BackgroundThe Pathogenesis of Alzheimer Disease: An Alternative to the Amyloid Hypothesis
Terry, R. D. (1996) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199655100-00001 · Cited by 291
Alzheimer's disease: a correlative study.
Neary, D., Snowden, J. S., Mann, D. M. A., Bowen, D. M., Sims, N. R., Northen, B., Yates, P. O., & DAVISON, A. N. (1986) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.49.3.229 · Cited by 277 · cited 1×
“Its activity is 40–90% lower in AD brains than in control brains, and this reduction correlates with cognitive decline (Perry et al., 1978; Davies, 1979; Wilcock et al., 1982; Sims et al., 1983; Neary et al., 1986; Bierer et al., 1995; Samuel et al., 1997; Cummings, 2000).”
BackgroundNathan, B. P., Chang, K.-C., Bellosta, S., Brisch, E., Ge, N., Mahley, R. W., & Pitas, R. E. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.34.19791 · Cited by 276 · cited 1×
“…extension (Nathan et al., 1994; Holtzman and Fagan, 1998) and synapse formation (Mauch et al., 2001), stabilization of microtubules (Strittmatter et al., 1994; Nathan et al., 1995) and endosomal–lysosomal membranes (Ji et al., 2002), and protection against oxidative stress (Miyata and Smith, 1996).”
BackgroundGenetic Neurodegenerative Diseases: The Human Illness and Transgenic Models
Price, D. L., Sisodia, S. S., & Borchelt, D. (1998) · Science · doi:10.1126/science.282.5391.1079 · Cited by 258 · cited 1×
“…et al., 1993; Yankner, 1996; Klein et al., 2001), injected into the brain (Geula et al., 1998), or produced in neurons of transgenic mice (Games et al., 1995; Masliah et al., 1996, 2001; Nalbantoglu et al., 1997; Calhoun et al., 1998; Price et al., 1998; Hsia et al., 1999; Mucke et al., 2000).”
BackgroundGilmor, M. L., Erickson, J. D., Varoqui, H., Hersh, L. B., Bennett, D. A., Cochran, E. J., Mufson, E. J., & Levey, A. I. (1999) · The Journal of Comparative Neurology · doi:10.1002/(sici)1096-9861(19990906)411:4 · Cited by 243
Knowles, R. B., Wyart, C., Buldyrev, S. V., Cruz, L., Urbanc, B., Hasselmo, M. E., Stanley, H. E., & Hyman, B. T. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.9.5274 · Cited by 241
Astrocytes and Microglia Respond to Estrogen with Increased apoE mRNAin Vivoandin Vitro
Stone, D. J., Rozovsky, I., Morgan, T. E., Anderson, C. P., Hajian, H., & Finch, C. E. (1997) · Experimental Neurology · doi:10.1006/exnr.1996.6360 · Cited by 237 · cited 1×
“It is expressed at high levels in the brain and can be produced by diverse cell types, including neurons, astrocytes, and microglia (Boyles et al., 1985; Stone et al., 1997; Buttini et al., 1999; Xu et al., 1999, 2000; Dekroon and Armati, 2001).”
BackgroundApolipoprotein E and cognitive performance
Raber, J., Wong, D., Yu, G.-Q., Buttini, M., Mahley, R. W., Pitas, R. E., & Mucke, L. (2000) · Nature · doi:10.1038/35006165 · Cited by 237 · cited 10×
“ApoE3 and apoE4 have differential effects on A -dependent memory deficits in hAPP/apoE transgenic mice well before these mice develop amyloid deposits (Raber et al., 2000).”
BackgroundInfluentialSelf-citationHyman, B. T., West, H. L., Rebeck, G. W., Buldyrev, S. V., Mantegna, R. N., Ukleja, M., Havlin, S., & Stanley, H. E. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.8.3586 · Cited by 212 · cited 4×
“Studies of AD brains have identified a higher plaque burden in people with apoE4 than in people with apoE3 (Berr et al., 1994; Heinonen et al., 1995; Hyman et al., 1995; Ishii et al., 1997; Johnson et al., 1998; McNamara et al., 1998), and these observations have been confirmed in transgenic models…”
BackgroundInfluentialYeo, T. T. S., Chua-Couzens, J., Butcher, L. L., Bredesen, D. E., Cooper, J. D., Valletta, J. S., Mobley, W. C., & Longo, F. M. (1997) · Journal of Neuroscience · doi:10.1523/jneurosci.17-20-07594.1997 · Cited by 206 · cited 1×
“ChAT activity in the medial septum of 3–10 mice per genotype was determined by previously described procedures (Yeo et al., 1997).”
MethodIntroduction of human apolipoprotein E4 “domain interaction” into mouse apolipoprotein E
Raffaı̈, R. L., Dong, L., Farese, R. V., & Weisgraber, K. H. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.201279298 · Cited by 201
Farlow, M. R., Lahiri, D. K., Poirier, J., Davignon, J., Schneider, L., & Hui, S. L. (1998) · Neurology · doi:10.1212/wnl.50.3.669 · Cited by 199 · cited 2×
“The therapeutic effect of acetylcholinesterase inhibitors during early stages of AD suggests an early impairment of cholinergic functions (Cummings, 2000; Nakano et al., 2001), and there is evidence that the responsiveness to these compounds is influenced by apoE genotype (Farlow et al., 1998).”
BackgroundAndrogens Protect against Apolipoprotein E4-Induced Cognitive Deficits
Raber, J., Bongers, G., LeFevour, A., Buttini, M., & Mucke, L. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-12-05204.2002 · Cited by 187 · cited 1×
“Recent findings suggest that endogenous androgens protect singly transgenic male mice against apoE4-dependent behavioral deficits, and that this protection is relative rather than absolute (Raber et al., 2002).”
BackgroundSpecific Regional Transcription of Apolipoprotein E in Human Brain Neurons
Xu, P., Gilbert, J. R., Qiu, H.-L., Ervin, J. F., Rothrock‐Christian, T., Hulette, C., & Schmechel, D. E. (1999) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)65305-9 · Cited by 178 · cited 1×
“It is expressed at high levels in the brain and can be produced by diverse cell types, including neurons, astrocytes, and microglia (Boyles et al., 1985; Stone et al., 1997; Buttini et al., 1999; Xu et al., 1999, 2000; Dekroon and Armati, 2001).”
BackgroundJi, Z.-S., Miranda, R. D., Newhouse, Y. M., Weisgraber, K. H., Huang, Y., & Mahley, R. W. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m112109200 · Cited by 177 · cited 1×
“…extension (Nathan et al., 1994; Holtzman and Fagan, 1998) and synapse formation (Mauch et al., 2001), stabilization of microtubules (Strittmatter et al., 1994; Nathan et al., 1995) and endosomal–lysosomal membranes (Ji et al., 2002), and protection against oxidative stress (Miyata and Smith, 1996).”
BackgroundSelf-citationMemory deficits and cholinergic impairments in apolipoprotein E-deficient mice
Gordon, I., Grauer, E., Genis, I., Sehayek, E., & Michaelson, D. M. (1995) · Neuroscience Letters · doi:10.1016/0304-3940(95)12006-p · Cited by 172 · cited 2×
“…lack of murine apoE or expression of human A in the presence of murine apoE is also associated with age-dependent synaptic and cholinergic deficits (Games et al., 1995; Gordon et al., 1995; Masliah et al., 1995a,b, 1996, 2001; Buttini et al., 1999, 2000; Hsia et al., 1999; Mucke et al., 2000).”
BackgroundDementia with Lewy Bodies Versus Pure Alzheimer Disease
Samuel, W., Alford, M. F., Hofstetter, C. R., & Hansen, L. A. (1997) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199705000-00006 · Cited by 167 · cited 3×
“We focused our analysis on SYN-IR presynaptic terminals, choline acetyltransferase (ChAT) activity, and cholinergic fibers, because decreases in these parameters correlate well with cognitive decline in AD (Terry et al., 1991; Samuel et al., 1997; Sze et al., 1997; Brown et al., 1998).”
BackgroundSoininen, H. S., Kosunen, O., Helisalmi, S., Mannermaa, A., Paljärvi, L., Talasniemi, S., Ryynänen, M., & Riekkinen, P. J. (1995) · Neuroscience Letters · doi:10.1016/0304-3940(95)11343-6 · Cited by 162 · cited 1×
“…have been detected primarily in later stages of the disease, and their modification by apoE isoforms remains controversial (Poirier et al., 1995; Soininen et al., 1995; Allen et al., 1997; Arendt et al., 1997; Salehi et al., 1998; Gilmor et al., 1999; Bronfman et al., 2000; Corey-Bloom et al.,…”
BackgroundCholinergic Changes in the APP23 Transgenic Mouse Model of Cerebral Amyloidosis
Boncristiano, S., Calhoun, M. E., Kelly, P. H., Pfeifer, M., Bondolfi, L., Stalder, M., Phinney, A. L., Abramowski, D., Sturchler-Pierrat, C., Enz, A., et al. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-08-03234.2002 · Cited by 160
Tolar, M., Keller, J. N., Chan, S., Mattson, M. P., Marques, M. A., & Crutcher, K. A. (1999) · The Journal of Neuroscience · doi:10.1523/jneurosci.19-16-07100.1999 · Cited by 148 · cited 1×
“However, it could also reflect the gain of an adverse activity that counteracts or interferes with beneficial activities of the holoprotein (Raber et al., 1998, 2000; Tolar et al., 1999; Buttini et al., 2000; Huang et al., 2001).”
BackgroundNeurotransmitters in basal ganglia and cortex of Alzheimer's disease with and without Lewy bodies
Langlais, P. J., Thai, L., Hansen, L. A., Galasko, D., Alford, M. F., & Masliah, E. (1993) · Neurology · doi:10.1212/wnl.43.10.1927 · Cited by 144 · cited 1×
“Because synaptic deficits correlate well with the development of cognitive deficits in AD (DeKosky and Scheff, 1990; Terry et al., 1991; Langlais et al., 1993; Samuel et al., 1997; Sze et al., 1997; Brown et al., 1998), the differential effects of apoE3 and apoE4 identified here might relate…”
BackgroundApolipoprotein E Isoform-Specific Differences in Outcome from Focal Ischemia in Transgenic Mice
Sheng, H., Laskowitz, D. T., Bennett, E. R., Schmechel, D. E., Bart, R. D., Saunders, A. M., Pearlstein, R. D., Roses, A. D., & Warner, D. S. (1998) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-199804000-00003 · Cited by 143 · cited 1×
“…al., 1998; McNamara et al., 1998; Holtzman et al., 2000a,b) but also in their capacity to protect the brain against diverse injuries, including those elicited by excitotoxins, ischemia, and trauma (E3 E4) (Sheng et al., 1998; Buttini et al., 1999, 2000; Horsburgh et al., 2000; Sabo et al., 2000).”
BackgroundGreenwood, P. M., Sunderland, T., Friz, J., & Parasuraman, R. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.21.11661 · Cited by 136 · cited 3×
“…effects of apoE3 and apoE4 on the development of AD manifestations were apparent primarily during early but not late stages of the aging process (Farrer et al., 1997; Bookheimer et al., 2000; Greenwood et al., 2000; Small et al., 2000; Yaffe et al., 2000; Chapman et al., 2001; Reiman et al., 2001).”
BackgroundJi, Z.-S., Pitas, R. E., & Mahley, R. W. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.22.13452 · Cited by 134 · cited 1×
“The 112Cys3Arg substitution, which differentiates apoE4 from apoE3, affects many aspects of apoE, including its conformation, stability, and binding to lipids and other molecules (Dong and Weisgraber, 1996; Ji et al., 1998; Huang et al., 2001; Raffaı̈ et al., 2001).”
BackgroundFarrer, L. A. (1997) · JAMA · doi:10.1001/jama.1997.03550160069041 · Cited by 124 · cited 5×
“In humans, apoE occurs in three major isoforms, which are associated with different risks of developing AD (E4 E3 E2) (Corder et al., 1993; Farrer et al., 1997).”
BackgroundInfluentialThe decline in synapses and cholinergic activity is asynchronous in Alzheimer’s disease
Tiraboschi, P., Hansen, L. A., Alford, M. F., Masliah, E., Thal, L. J., & Corey‐Bloom, J. (2000) · Neurology · doi:10.1212/wnl.55.9.1278 · Cited by 122 · cited 2×
“However, biochemical and neuropathological alterations of the cholinergic system have been detected primarily in later stages of the disease, and their modification by apoE isoforms remains controversial (Poirier et al., 1995; Soininen et al., 1995; Allen et al., 1997; Arendt et al., 1997; Salehi et al., 1998; Gilmor…”
BackgroundAβ‐peptide length aid apolipoprotein E genotype in Alzheimer's disease
Gearing, M., Mori, H., & Mirra, S. S. (1996) · Annals of Neurology · doi:10.1002/ana.410390320 · Cited by 120 · cited 1×
“…in their effects on A deposition (E4 E3) (Rebeck et al., 1993; Schmechel et al., 1993; Berr et al., 1994; Heinonen et al., 1995; Hyman et al., 1995; Gearing et al., 1996; Ishii et al., 1997; Johnson et al., 1998; McNamara et al., 1998; Holtzman et al., 2000a,b) but also in their capacity to…”
BackgroundPreclinical memory decline in cognitively normal apolipoprotein E–ε4 homozygotes
Caselli, R. J., Graff‐Radford, N. R., Reiman, E. M., Weaver, A., Osborne, D., Lucas, J. A., Uecker, A., & Thibodeau, S. N. (1999) · Neurology · doi:10.1212/wnl.53.1.201 · Cited by 120 · cited 1×
“…4 alleles but without overt AD revealed decreased brain activity, decreased visual attention, and subtle memory impairments in 4 carriers compared with people with other APOE alleles (Caselli et al., 1999; Bookheimer et al., 2000; Greenwood et al., 2000; Small et al., 2000; Reiman et al., 2001).”
BackgroundDonepezil hydrochloride preserves regional cerebral blood flow in patients with Alzheimer's disease.
Nakano, S., Asada, T., Matsuda, H., Uno, M., & Takasaki, M. (2001) · PubMed · Cited by 112
Alzheimer Aβ neurotoxicity: Promotion by antichymotrypsin, ApoE4; inhibition by Aβ-related peptides
Ma, J., Brewer, H. B., & Potter, H. (1996) · Neurobiology of Aging · doi:10.1016/0197-4580(96)00112-1 · Cited by 108 · cited 1×
“This finding may be consistent with the notion that the formation of neurotoxic A species depends on the association of A with “pathological molecular chaperones,” such as apoE and apoJ (Wisniewski and Frangione, 1992; Oda et al., 1995; Ma et al., 1996; Permanne et al., 1997).”
ResultSabo, T., Lomnitski, L., Nyska, A., Beni, S., Maronpot, R. R., Shohami, E., Roses, A. D., & Michaelson, D. M. (2000) · Neuroscience · doi:10.1016/s0306-4522(00)00438-3 · Cited by 104 · cited 1×
“…al., 1998; McNamara et al., 1998; Holtzman et al., 2000a,b) but also in their capacity to protect the brain against diverse injuries, including those elicited by excitotoxins, ischemia, and trauma (E3 E4) (Sheng et al., 1998; Buttini et al., 1999, 2000; Horsburgh et al., 2000; Sabo et al., 2000).”
BackgroundButtini, M., Akeefe, H., Lin, C. J., Mahley, R. W., Pitas, R. E., Wyss‐Coray, T., & Mucke, L. (2000) · Neuroscience · doi:10.1016/s0306-4522(00)00069-5 · Cited by 98 · cited 5×
“2) (Masliah et al., 1995b; Buttini et al., 1999, 2000; Hsia et al., 1999; Mucke et al., 2000).”
BackgroundInfluentialAllen, S. J., MacGowan, S. H., Tyler, S., Wilcock, G., Robertson, A., Holden, P., Smith, S. K. F., & Dawbarn, D. (1997) · Neuroscience Letters · doi:10.1016/s0304-3940(97)00872-0 · Cited by 86 · cited 2×
“…in later stages of the disease, and their modification by apoE isoforms remains controversial (Poirier et al., 1995; Soininen et al., 1995; Allen et al., 1997; Arendt et al., 1997; Salehi et al., 1998; Gilmor et al., 1999; Bronfman et al., 2000; Corey-Bloom et al., 2000; Tiraboschi et…”
BackgroundIshii, K., Tamaoka, A., Mizusawa, H., Shoji, S.-I., Ohtake, T., Fraser, P. E., Takahashi, H., Tsuji, S., Gearing, M., Mizutani, T., et al. (1997) · Brain Research · doi:10.1016/s0006-8993(96)01363-7 · Cited by 85 · cited 3×
“…have identified a higher plaque burden in people with apoE4 than in people with apoE3 (Berr et al., 1994; Heinonen et al., 1995; Hyman et al., 1995; Ishii et al., 1997; Johnson et al., 1998; McNamara et al., 1998), and these observations have been confirmed in transgenic models expressing these…”
BackgroundSchmidt, M. L., Robinson, K. A., Lee, V. M., & Trojanowski, J. Q. (1995) · Europe PMC (PubMed Central) · Cited by 71
Berr, C., Hauw, J., Delaère, P., Duyckaerts, C. J., & Amouyel, P. (1994) · Neuroscience Letters · doi:10.1016/0304-3940(94)90763-3 · Cited by 69 · cited 4×
“ApoE4 increases the plaque burden not only in people with AD but also in nondemented individuals (Berr et al., 1994), underlining the potential dissociation between its effects on amyloid deposition and AD risk/onset.”
BackgroundInfluentialBrown, D. F., Risser, R. C., Bigio, E. H., Tripp, P., Stiegler, A., Welch, E., Eagan, K. P., Hladik, C. L., & White, C. L. (1998) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199810000-00007 · Cited by 69 · cited 2×
“…development of cognitive deficits in AD (DeKosky and Scheff, 1990; Terry et al., 1991; Langlais et al., 1993; Samuel et al., 1997; Sze et al., 1997; Brown et al., 1998), the differential effects of apoE3 and apoE4 identified here might relate closely to the effects of these isoforms on AD risk (E4…”
BackgroundIsolation and Characterization of Apolipoproteins from Murine Microglia
Xu, Q., Li, Y., Cyras, C., Sanan, D. A., & Cordell, B. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m002796200 · Cited by 69
Horsburgh, K. J., McCulloch, J., Nilsen, M., Roses, A. D., & Nicoll, J. A. R. (2000) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2000.01339.x · Cited by 68 · cited 1×
“…al., 1998; McNamara et al., 1998; Holtzman et al., 2000a,b) but also in their capacity to protect the brain against diverse injuries, including those elicited by excitotoxins, ischemia, and trauma (E3 E4) (Sheng et al., 1998; Buttini et al., 1999, 2000; Horsburgh et al., 2000; Sabo et al., 2000).”
BackgroundThe effects of APOE genotype on age at onset and progression of neurodegenerative diseases
Chapman, J., Korczyn, A. D., Karussis, D. M., & Michaelson, D. M. (2001) · Neurology · doi:10.1212/wnl.57.8.1482 · Cited by 67 · cited 3×
“As in our mouse models, the differential effects of apoE3 and apoE4 on the development of AD manifestations were apparent primarily during early but not late stages of the aging process (Farrer et al., 1997; Bookheimer et al., 2000; Greenwood et al., 2000; Small et al., 2000; Yaffe et al., 2000; Chapman et al., 2001;…”
BackgroundCaselli, R. J., Osborne, D., Reiman, E. M., Hentz, J. G., Barbieri, C. J., Saunders, A. M., Hardy, J., Graff‐Radford, N. R., Hall, G. R., & Alexander, G. E. (2001) · Journal of the Neurological Sciences · doi:10.1016/s0022-510x(01)00577-9 · Cited by 62 · cited 1×
“…relatively little impact on the severity and progression of neuronal deficits in old age and during later stages of AD (Farrer et al., 1997; Bookheimer et al., 2000; Greenwood et al., 2000; Small et al., 2000; Yaffe et al., 2000; Caselli et al., 2001; Chapman et al., 2001; Reiman et al., 2001).”
BackgroundApolipoprotein E Genotype and Deposits of Aβ40 and Aβ42 in Alzheimer Disease
McNamara, M. J., Gómez‐Isla, T., & Hyman, B. T. (1998) · Archives of Neurology · doi:10.1001/archneur.55.7.1001 · Cited by 55 · cited 3×
“…et al., 1993; Berr et al., 1994; Heinonen et al., 1995; Hyman et al., 1995; Gearing et al., 1996; Ishii et al., 1997; Johnson et al., 1998; McNamara et al., 1998; Holtzman et al., 2000a,b) but also in their capacity to protect the brain against diverse injuries, including those elicited…”
BackgroundSalehi, A., Dubelaar, E. J. G., Mulder, M. T., & Swaab, D. F. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.19.11445 · Cited by 53 · cited 2×
“However, biochemical and neuropathological alterations of the cholinergic system have been detected primarily in later stages of the disease, and their modification by apoE isoforms remains controversial (Poirier et al., 1995; Soininen et al., 1995; Allen et al., 1997; Arendt et al., 1997; Salehi et al., 1998; Gilmor…”
BackgroundAlzheimer pathology of patients carrying apoliprotein E ε4 allele
Heinonen, O. (1995) · Neurobiology of Aging · doi:10.1016/0197-4580(95)00076-q · Cited by 52 · cited 3×
“Studies of AD brains have identified a higher plaque burden in people with apoE4 than in people with apoE3 (Berr et al., 1994; Heinonen et al., 1995; Hyman et al., 1995; Ishii et al., 1997; Johnson et al., 1998; McNamara et al., 1998), and these observations have been confirmed in transgenic models…”
BackgroundPermanne, B., Perez, C., Soto, C., Frangione, B., & Wisniewski, T. (1997) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1997.7727 · Cited by 49 · cited 1×
“This finding may be consistent with the notion that the formation of neurotoxic A species depends on the association of A with “pathological molecular chaperones,” such as apoE and apoJ (Wisniewski and Frangione, 1992; Oda et al., 1995; Ma et al., 1996; Permanne et al., 1997).”
ResultTacrine and rate of progression in Alzheimer's disease – relation to ApoE allele genotype
Sjögren, M. J. C., Hesse, C., Basun, H., Ganesh Kumar, K. O. L., Thostrup, H., Kilander, L., Marcusson, J. O., Edman, Å., Wallin, A., Karlsson, I., et al. (2001) · Journal of Neural Transmission · doi:10.1007/s007020170066 · Cited by 48 · cited 2×
“However, biochemical and neuropathological alterations of the cholinergic system have been detected primarily in later stages of the disease, and their modification by apoE isoforms remains controversial (Poirier et al., 1995; Soininen et al., 1995; Allen et al., 1997; Arendt et al., 1997; Salehi et al., 1998; Gilmor…”
BackgroundCho, S., Kim, Y., Cruz, M. O., Park, E., Chu, C. K., Song, G., & JOH, T. H. (2001) · Glia · doi:10.1002/1098-1136(20010315)33:4 · Cited by 39
Davis, J. N., & Chisholm, J. C. (1997) · Trends in Neurosciences · doi:10.1016/s0166-2236(97)85989-9 · Cited by 39
Goedert, M., & Hasegawa, M. (1999) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)65242-x · Cited by 38
Hypolipidemic and Hyperlipidemic Phenotypes in Transgenic Mice Expressing Human Apolipoprotein E2
Huang, Y., Schwendner, S. W., Rall, S. C., & Mahley, R. W. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.46.29146 · Cited by 35 · cited 1×
“ApoE levels in brain tissues were quantitated by Western blot analysis as described previously (Huang et al., 1996, 2001).”
MethodE4 allele dosage does not predict cholinergic activity or synapse loss in Alzheimer’s disease
Corey‐Bloom, J., Tiraboschi, P., Hansen, L. A., Alford, M. F., Schoos, B., Sabbagh, M. N., Masliah, E., & Thal, L. J. (2000) · Neurology · doi:10.1212/wnl.54.2.403 · Cited by 34 · cited 2×
“However, biochemical and neuropathological alterations of the cholinergic system have been detected primarily in later stages of the disease, and their modification by apoE isoforms remains controversial (Poirier et al., 1995; Soininen et al., 1995; Allen et al., 1997; Arendt et al., 1997; Salehi et al., 1998; Gilmor…”
BackgroundJohnson, J. K., McCleary, R., Oshita, M. H., & Cotman, C. W. (1998) · Brain Research · doi:10.1016/s0006-8993(98)00363-1 · Cited by 32 · cited 3×
“…plaque burden in people with apoE4 than in people with apoE3 (Berr et al., 1994; Heinonen et al., 1995; Hyman et al., 1995; Ishii et al., 1997; Johnson et al., 1998; McNamara et al., 1998), and these observations have been confirmed in transgenic models expressing these human apoE isoforms in…”
BackgroundPotential Role of apoE in Structural Plasticity in the Nervous System
Holtzman, D. M., & Fagan, A. M. (1998) · Trends in Cardiovascular Medicine · doi:10.1016/s1050-1738(98)00017-6 · Cited by 30 · cited 1×
“…of apoE3 that might allow it to delay age- and A -dependent synaptic deficits include promotion of neurite extension (Nathan et al., 1994; Holtzman and Fagan, 1998) and synapse formation (Mauch et al., 2001), stabilization of microtubules (Strittmatter et al., 1994; Nathan et al., 1995)…”
BackgroundBronfman, F. C., Tesseur, I. C., Hofker, M. H., Havekens, L. M., & LEUVEN, F. V. (2000) · Neuroscience · doi:10.1016/s0306-4522(00)00016-6 · Cited by 27 · cited 2×
“However, biochemical and neuropathological alterations of the cholinergic system have been detected primarily in later stages of the disease, and their modification by apoE isoforms remains controversial (Poirier et al., 1995; Soininen et al., 1995; Allen et al., 1997; Arendt et al., 1997; Salehi et al., 1998; Gilmor…”
BackgroundAbnormal synaptic regeneration in hAPP transgenic and ApoE knockout mice
San Diego, C. A. (1994) · Neurobiology of Aging · doi:10.1016/0197-4580(94)92498-8 · Cited by 26
Kobayashi, K., Amemiya, S., Mochizuki, M., Kobayashi, K., Matsushita, K., Sawanobori, E., Ishihara, T., Higashida, K., Shimura, Y., Kato, K., et al. (1999) · Hormone Research in Paediatrics · doi:10.1159/000023358 · Cited by 18
The Pathogenesis of Alzheimer Disease: An Alternative to the Amyloid Hypothesis
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Alzheimerʼs disease. A correlative study
Neary, D., Snowden, J. S., Mann, D. M. A., Bowen, D. M., Sims, N. R., Northen, B., Yates, P. O., & DAVISON, A. N. (1987) · Alzheimer Disease & Associated Disorders · doi:10.1097/00002093-198701000-00024 · Cited by 6
Diagnostic criteria for primary progressive mutiple sclerosis: a position paper.
(2000) · Pure Amsterdam UMC · doi:10.1002/1531-8249(200006)47:6 · Cited by 2
Research works printed but not linked: 1
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Cited by
Sorted by citations
Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy
Liu, C.-C., Kanekiyo, T., Xu, H., & Bu, G. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2012.263 · Cited by 3,459
Alzheimer Mechanisms and Therapeutic Strategies
Huang, Y., & Mucke, L. (2012) · Cell · doi:10.1016/j.cell.2012.02.040 · Cited by 1,758
Self-citationThe 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
“Other studies using transgenic mice that possess different human apoE transgenes also demonstrate an isoform-specific difference (E4>E3) in Aβ deposition (Buttini et al., 2002; Dolev and Michaelson, 2004).”
BackgroundPickford, F., Masliah, E., Britschgi, M., Lucin, K., Narasimhan, R., Jaeger, P. A., Small, S., Spencer, B., Rockenstein, E., Levine, B., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci33585 · Cited by 268
Neurotoxicity of Amyloid -Protein: Synaptic and Network Dysfunction
Mucke, L., & Selkoe, D. J. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006338 · Cited by 1,000
Metadata
- Authors
- Buttini, M., Yu, G.-Q., Shockley, K., Huang, Y., Jones, B., Masliah, E., Mallory, M., Yeo, T., Longo, F. M., & Mucke, L.
- Affiliations
- Gladstone Institutes (US)
- University of California San Diego (US)
- San Francisco VA Medical Center (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2002-12-15
- Volume
- 22
- Issue
- 24
- Pages
- 10539-10548
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6758409
- OpenAlex
- W2100295360
- Cited by
- 183
- References
- 112
- Citations by year
- 2025: 5 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 8 · 2019: 6 · 2018: 4 · 2017: 5 · 2016: 2 · 2015: 9 · 2014: 2 · 2013: 9 · 2012: 9
- FWCI
- 8.98
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- Locations
- Journal of Neuroscience (publishedVersion, public-domain)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association
- National Institutes of Health (AG11385)
- National Institute on Aging (AG-11385, R37AG011385, R01AG011385)
- National Cancer Institute (R01CA094141)
- National Institute of Neurological Disorders and Stroke (NS41787, R01NS041787)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- apolipoprotein E, APOE ε4, APOE3, Alzheimer's disease, amyloid-beta, amyloid plaques, synaptic deficits, cholinergic deficit, choline acetyltransferase, synaptophysin, brain aging, amyloid precursor protein, transgenic mice, hippocampus, neocortex
- MeSH terms
- Age Factors, Alzheimer Disease, Animals, Apolipoproteins E, Brain, Choline O-Acetyltransferase, Cholinergic Fibers, Humans, Immunohistochemistry, Mice, Transgenic, Peptide Fragments, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Synaptophysin, Presynaptic Terminals, Protein Isoforms, Mice, Apolipoprotein E3, Apolipoprotein E4
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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