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ApoE isoform-dependent changes in hippocampal synaptic function - PubMed

  • ️Thu Jan 01 2009

ApoE isoform-dependent changes in hippocampal synaptic function

Kimberly M Korwek et al. Mol Neurodegener. 2009.

Abstract

The lipoprotein receptor system in the hippocampus is intimately involved in the modulation of synaptic transmission and plasticity. The association of specific apoE isoform expression with human neurodegenerative disorders has focused attention on the role of these apoE isoforms in lipoprotein receptor-dependent synaptic modulation. In the present study, we used the apoE2, apoE3 and apoE4 targeted replacement (TR) mice along with recombinant human apoE isoforms to determine the role of apoE isoforms in hippocampus area CA1 synaptic function. While synaptic transmission is unaffected by apoE isoform, long-term potentiation (LTP) is significantly enhanced in apoE4 TR mice versus apoE2 TR mice. ApoE isoform-dependent differences in LTP induction require NMDA-receptor function, and apoE isoform expression alters activation of both ERK and JNK signal transduction. Acute application of specific apoE isoforms also alters LTP induction while decreasing NMDA-receptor mediated field potentials. Furthermore, acute apoE isoform application does not have the same effects on ERK and JNK activation. These findings demonstrate specific, isoform-dependent effects of human apoE isoforms on adult hippocampus synaptic plasticity and highlight mechanistic differences between chronic apoE isoform expression and acute apoE isoform exposure.

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Figures

Figure 1
Figure 1

ApoE4 TR animals show increased LTP induction without changes in synaptic transmission. A) Input-output curve generated from the slope fEPSP versus fiber volley amplitude measured at increasing stimulus intensities. B) Paired pulse facilitation. Second stimuli delivered at 20 ms intervals from 20 to 300 ms from first stimuli. Percent facilitation of fEPSP slope of second response as percentage of first response. C) Long-term potentation induced by 5 trains of theta-burst stimulation (arrow). Expressed as slope of fEPSP, standardized to the first 20 minutes of recording. Representative traces 5 minutes before (black lines) and 40 minutes after (colored lines) stimulation for apoE4 (red) and apoE2 TR (blue). Scale: 0.5 mV, 2 ms. D) Average potentiation of last 20 minutes of recording. C57BL/6J = WT, green diamond, n = 12; apoE-deficient = E0, Black circle, n = 12; apoE2 TR = E2, blue square, n = 17; apoE3 TR = E3, purple inverted triangle, n = 6; apoE4 TR = E4, red triangle, n = 14. Data expressed as mean ± SEM. *p < 0.05, ANOVA with Bonferroni's posttest.

Figure 2
Figure 2

Acute recombinant apoE isoform application recapitulates alterations in LTP induction. Application of 100 nM recombinant human apoE isoforms 5 min prior to start of recording. A) Paired pulse facilitation. Second stimuli delivered at 20 ms intervals from 20 to 300 ms from first stimuli. Percent facilitation of fEPSP slope of second response as percentage of first response. B) Long-term potentiation induced by 5 trains of theta-burst stimulation (arrow). Expressed as slope of fEPSP, standardized to the first 20 minutes of recording. C) Average potentiation of last 20 minutes of recording. control = black circle, n = 8; rhapoE2 = blue square n = 8; rhapoE3 = purple inverted triangle, n = 7; rhapoE4 = red triangle, n = 6. Data expressed as mean ± SEM. *p < 0.05, ANOVA with Bonferroni's posttest.

Figure 3
Figure 3

NMDA receptor-independent LTP is not affected by apoE isoform. A) Long term potentiation induced by 2 trains of 200 Hz stimulation (arrow). Application of 100 μM APV for 5 minutes before and 20 minutes after 200 Hz stimulation. Expressed as slope of fEPSP, standardized to the first 20 minutes of recording. B) Average potentiation of last 20 minutes of recording. C57BL/6J = WT, green diamond, n = 5; apoE-deficient = E0, black circle n = 8; apoE2 TR = E2, blue square, n = 8; apoE3 TR = E3, purple inverted triangle, n = 7; apoE4 TR = E4, red triangle, n = 6. Data expressed as mean ± SEM.

Figure 4
Figure 4

ApoE isoforms alter NMDA receptor-dependent field potentials. A) Synaptic transmission in the presence of 20 μM CNQX (dashed line) and 100 nM human apoE (solid line). Expressed as slope of fEPSP, standardized to the first 20 minutes of recording. B) Average potentiation of last 20 minutes of recording. control = black circle, n = 8; rhapoE2 = blue square, n = 8; rhapoE3 = purple inverted triangle, n = 7; rhapoE4 = red triangle, n = 6. Data expressed as mean ± SEM. *p < 0.05, **p < 0.01, ANOVA with Bonferroni's posttest.

Figure 5
Figure 5

ApoE isoform expression does not affect apoER2 expression levels. Representative western blots showing levels of apoE (A) and apoER2 (B) immunoreactivity in whole hippocampus of aged animals. Quantification of immunoreactivity standardized to actin (n = 8, n = 5 for apoE3 TR). C57BL/6J (WT, white), apoE-deficient (E0, light grey), apoE2 TR (E2, medium grey), apoE3 TR (E3, dark grey), apoE4 TR (E4, black). Data expressed as mean ± SEM.

Figure 6
Figure 6

Effect of chronic apoE isoform expression on NR2A, NR2B levels and tyrosine phosphorylation. A) Levels of NR2A immunoreactivity, standardized to NR1 immunoreactivity, from CA1 of apoE TR animals. B) Levels of NR2B immunoreactivity, standardized to NR1 immunoreactivity, from CA1 of apoE TR animals. C) Levels of phosphotyrosine immunoreactivity at the molecular weight corresponding to NR2A and NR2B from CA1 of apoE TR animals. apoE2 TR (E2, medium grey), apoE3 TR (E3, dark grey), apoE4 TR (E4, black). Data expressed as mean ± SEM.

Figure 7
Figure 7

Effect of acute apoE exposure on NR2A and NR2B tyrosine phosphorylation. ApoE-deficient slices treated with 100 nM rhapoE isoforms. A) Ratio of pNR2A as measured by pTyr immunoreactivity to NR2A immunoreactivity as immunoprecipatated by NR2A. B) Ratio of pNR2B as measured by pTyr immunoreactivity to NR2B immunoreactivity as immunoprecipatated by NR2B. control (C, light grey), rhapoE2 (E2, medium grey), rhapoE3 (E3, dark grey), rhapoE4 (E4, black). Data expressed as mean ± SEM.

Figure 8
Figure 8

Chronic apoE isoform expression alters activation of ERK1/2 and JNK1/2. A) Quantification of levels of pERK (i) or ERK (ii) immunoreactivity in CA1 of apoE TR, wild-type, and apoE deficient animals. iii) pERK/ERK ratio. B) Quantification of levels of pJNK (i) or JNK (ii) immunoreactivity in CA1 of apoE TR, wild-type, or apoE deficient animals. iii) pJNK/JNK ratio. Quantification of immunoreactivity normalized to background (n = 5). C57BL/6J (WT, white), apoE-deficient (E0, light grey), apoE2 TR (E2, medium grey), apoE3 TR (E3, dark grey), apoE4 TR (E4, black). Data expressed as mean ± SEM. *p < 0.05, ANOVA with Bonferroni's posttest.

Figure 9
Figure 9

Effects of acute apoE isoform exposure on ERK1/2 and JNK1/2 activation. Quantification of A) pERK/ERK rato and B) pJNK/JNK ratio in CA1 of apoE-deficient animals treated with 100 nM rhapoE isoforms (n = 6 for each). Representative western blots showing levels of pERK, ERK, pJNK, JNK, and actin. control (C, light grey), rhapoE2 (E2, medium grey), rhapoE3 (E3, dark grey), rhapoE4 (E4, black). Data expressed as mean ± SEM.

Figure 10
Figure 10

Model of chronic apoE signaling in adult hippocampus. Reelin interacts exclusively with the lipoprotein receptors apoER2 and VLDLR, with a much higher affinity for apoER2. ApoE binds to all lipoprotein receptors and undergoes endocytosis. Chronic apoE4 exposure enhances ERK1/2 activation, likely through interactions with the LRP1 receptor. In contrast, chronic apoE2 and apoE3 expression reduce activation of JNK1/2 and ERK1/2 activation. Together with proper NMDAR function, these changes culminate in alterations in LTP induction with chronic apoE2 isoform expression.

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