Increased tau Phosphorylation in Apolipoprotein E4 Transgenic Mice Is Associated with Activation of Extracellular Signal-regulated Kinase

Harris, Faith M.; Brecht, Walter J.; Xu, Qin; Mahley, Robert W.; Huang, Yadong

doi:10.1074/jbc.m408127200

Cited by 151Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Increased tau Phosphorylation in Apolipoprotein E4 Transgenic Mice Is Associated with Activation of Extracellular Signal-regulated Kinase

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Harris, Faith M., Brecht, Walter J., Xu, Qin, Mahley, Robert W., Huang, Yadong·2004·Journal of Biological Chemistry

DOI 10.1074/jbc.m408127200

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Abstract

Although apolipoprotein (apo) E4 is present in amyloid plaques and neurofibrillary tangles, its pathogenic role in Alzheimer's disease (AD) is unclear. Neuronal expression of apoE4 or apoE4 fragments in transgenic mice increases tau phosphorylation. To identify the kinase responsible for the increase, we studied transgenic mice expressing human apoE3 or apoE4 in neurons under the control of the neuron-specific enolase promoter. Brain levels of phosphorylated tau (p-tau) and phosphorylated (active) extracellular signal-regulated kinase (p-Erk) increased with age in both groups but were considerably higher in the apoE4 mice. Other candidate kinases, including glycogen synthase kinase 3beta and cyclin-dependent kinase-5 and its activators p25 and p35, were not significantly altered. The increases in p-Erk and p-tau were highest in the hippocampus, intermediate in the cortex, and lowest in the cerebellum. In the hippocampus, p-Erk and p-tau accumulated in the hilus and CA3 region of the dentate gyrus, where high levels of zinc are found along mossy fibers. In Neuro-2a cells stably expressing apoE3 or apoE4, treatment with ZnCl2 generated 2-fold more p-Erk and 3-fold more p-tau in the apoE4-expressing cells. Phosphorylation of Erk and tau was reduced by preincubation with the Erk pathway inhibitor U0126. Thus, increased tau phosphorylation in apoE4 transgenic mice was associated with Erk activation and could be modified by zinc, suggesting that apoE4 and zinc act in concert to contribute to the pathogenesis of AD.

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APOE4 exacerbates AD-related pathologies, including amyloid-beta plaques, Tau tangles, neurodegeneration and neuroinflammation.
“It exacerbates AD-related pathologies, including amyloid-beta (Aβ) plaques, Tau tangles, neurodegeneration and neuroinflammation4–16.”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [5]
Animal and cell models of tauopathies have revealed that APOE4 is associated with a greater burden of misfolded and hyperphosphorylated tau and more severe tau-induced neurodegeneration, both in the presence and in the absence of Aβ.
“Although for many years the effects of APOE on tau were assumed to be mediated through Aβ, animal and cell models of tauopathies have revealed that APOE4 is associated with a greater burden of misfolded and hyperphosphorylated tau and more severe tau-induced neurodegeneration, both in the presence and in the absence of Aβ125,126.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [126]
Alternatively, the effects of apoE on tau phosphorylation could be explained by an intracellular signaling pathway induced by apoE, rather than the direct interaction between apoE and tau.
“Alternatively, the effects of apoE on tau phosphorylation could be explained by an intracellular signaling pathway induced by apoE (Harris et al., 2004; Hoe et al., 2005a), rather than the direct interaction between apoE and tau.”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Harris et al., 2004
Specific overexpression of human ApoE4 in neurons, but not astrocytes, increases tau phosphorylation in mouse brains compared to ApoE3 overexpression.
“Specific overexpression of human ApoE4 in neurons, but not astrocytes, increases tau phosphorylation in mouse brains compared to ApoE3 overexpression128,129.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [128]

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Authors: Harris, F. M., Brecht, W. J., Xu, Q., Mahley, R. W., & Huang, Y.
Affiliations: Gladstone Institutes (US)
Corresponding author: Huang, Yadong
ORCID: Harris, Faith M.
Xu, Qin
Mahley, Robert W.
Huang, Yadong
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2004-10
Volume: 279
Issue: 43
Pages: 44795-44801
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m408127200
OpenAlex: W1985043600
Cited by: 151
References: 97
Citations by year: 2026: 1 · 2025: 8 · 2024: 10 · 2023: 9 · 2022: 9 · 2021: 6 · 2020: 6 · 2019: 8 · 2018: 10 · 2017: 3 · 2016: 8 · 2015: 5 · 2014: 8 · 2013: 10 · 2012: 7
FWCI: 3.29
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 5870 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: National Institute on Aging (P01AG022074)
National Heart, Lung, and Blood Institute (R01 HL37063, R01HL037063)
National Institute of Neurological Disorders and Stroke (R21NS046465)
Topics: Health Sciences › Medicine › Physiology › 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: APOE ε4, tau phosphorylation, extracellular signal-regulated kinase, Alzheimer's disease, zinc, ERK signaling, transgenic mice, hippocampus, mossy fibers, glycogen synthase kinase-3β, cyclin-dependent kinase 5, neurofibrillary tangles, amyloid plaques
MeSH terms: Glycogen Synthase Kinase 3 beta, Animals, Apolipoproteins E, Brain, Butadienes, Cell Line, Cerebellum, Cerebral Cortex, Dose-Response Relationship, Drug, Enzyme Activation, Enzyme Inhibitors, Genotype, Hippocampus, Immunohistochemistry, Mice, Transgenic, Nerve Tissue Proteins, Neurons, Nitriles, Phosphorylation, Time Factors, Transfection, Zinc, Blotting, Western, tau Proteins, Cyclin-Dependent Kinases, Glycogen Synthase Kinase 3, Cell Line, Tumor, MAP Kinase Kinase 2, Cyclin-Dependent Kinase 5, Mice, Apolipoprotein E4

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Increased tau Phosphorylation in Apolipoprotein E4 Transgenic Mice Is Associated with Activation of Extracellular Signal-regulated Kinase

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