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Exosomes neutralize synaptic-plasticity-disrupting activity of Aβ assemblies in vivo.

An K, Klyubin I, Kim Y, Jung JH, Mably AJ, O'Dowd ST, Lynch T, Kanmert D, Lemere CA, Finan GM, Park JW, Kim TW, Walsh DM, Rowan MJ, Kim JH - Mol Brain (2013)

Bottom Line: We here provide in vivo evidence that exosomes derived from N2a cells or human cerebrospinal fluid can abrogate the synaptic-plasticity-disrupting activity of both synthetic and AD brain-derived Aβ.Mechanistically, this effect involves sequestration of synaptotoxic Aβ assemblies by exosomal surface proteins such as PrPC rather than Aβ proteolysis.These data suggest that exosomes can counteract the inhibitory action of Aβ, which contributes to perpetual capability for synaptic plasticity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Gyungbuk 790-784, Korea. joungkim@postech.ac.kr.

ABSTRACT

Background: Exosomes, small extracellular vesicles of endosomal origin, have been suggested to be involved in both the metabolism and aggregation of Alzheimer's disease (AD)-associated amyloid β-protein (Aβ). Despite their ubiquitous presence and the inclusion of components which can potentially interact with Aβ, the role of exosomes in regulating synaptic dysfunction induced by Aβ has not been explored.

Results: We here provide in vivo evidence that exosomes derived from N2a cells or human cerebrospinal fluid can abrogate the synaptic-plasticity-disrupting activity of both synthetic and AD brain-derived Aβ. Mechanistically, this effect involves sequestration of synaptotoxic Aβ assemblies by exosomal surface proteins such as PrPC rather than Aβ proteolysis.

Conclusions: These data suggest that exosomes can counteract the inhibitory action of Aβ, which contributes to perpetual capability for synaptic plasticity.

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Related in: MedlinePlus

Exosomes abrogate ADDL-mediated disruption of LTP. (A) Prior infusion of exosomes (4 μg in 5 μl, asterisk) prevented ADDLs (10 pmol in 5 μl, hash) inhibiting LTP. Animals received sequential injections of exosomes and ADDLs before the application of HFS (arrow). Insets show representative traces at the color-matched time points. Calibrations: 1.5 mV and 10 ms for all traces. (B) Dose-dependent protective effect of exosomes against ADDL-mediated disruption of LTP (0 μg Exo + ADDL, 100 ± 3%, n = 5; 0.2 μg Exo + ADDL, 105 ± 5%, n = 4; 1 μg Exo + ADDL, 123 ± 5%, n = 4; 4 μg Exo + ADDL, 151 ± 10%, n = 6; 10 μg Exo + ADDL, 168 ± 9%, n = 4). Statistical significance was expressed as **, P < 0.01 comparing to control group injected with 0 μg Exo + ADDL. (C) Neither exosomes nor ADDLs (5 μl, asterisk) affected baseline excitatory synaptic transmission in the CA1 area in vivo (PBS, n = 4; ADDL, n = 5; Exo, n = 4). (D) Exosomes (4 μg in 5 μl, asterisk) did not enhance decremental or standard LTP. An arrow indicates the time point of application of either weak HFS for decremental LTP or HFS for standard LTP, respectively. Insets and calibrations as in A. Error bars, ± SEM.
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Figure 2: Exosomes abrogate ADDL-mediated disruption of LTP. (A) Prior infusion of exosomes (4 μg in 5 μl, asterisk) prevented ADDLs (10 pmol in 5 μl, hash) inhibiting LTP. Animals received sequential injections of exosomes and ADDLs before the application of HFS (arrow). Insets show representative traces at the color-matched time points. Calibrations: 1.5 mV and 10 ms for all traces. (B) Dose-dependent protective effect of exosomes against ADDL-mediated disruption of LTP (0 μg Exo + ADDL, 100 ± 3%, n = 5; 0.2 μg Exo + ADDL, 105 ± 5%, n = 4; 1 μg Exo + ADDL, 123 ± 5%, n = 4; 4 μg Exo + ADDL, 151 ± 10%, n = 6; 10 μg Exo + ADDL, 168 ± 9%, n = 4). Statistical significance was expressed as **, P < 0.01 comparing to control group injected with 0 μg Exo + ADDL. (C) Neither exosomes nor ADDLs (5 μl, asterisk) affected baseline excitatory synaptic transmission in the CA1 area in vivo (PBS, n = 4; ADDL, n = 5; Exo, n = 4). (D) Exosomes (4 μg in 5 μl, asterisk) did not enhance decremental or standard LTP. An arrow indicates the time point of application of either weak HFS for decremental LTP or HFS for standard LTP, respectively. Insets and calibrations as in A. Error bars, ± SEM.

Mentions: In agreement with prior reports [5], high-frequency stimulation (HFS) failed to trigger robust LTP in anesthetized rats that had received i.c.v. injection of ADDLs (PBS + ADDL, 105 ± 6%, n = 4 vs. PBS + PBS, 166 ± 10%, n = 4 at 3 h post-HFS, P < 0.001, one-way ANOVA with post hoc Tukey; Figure 2A). Somewhat unexpectedly, prior infusion of 4 μg exosomes markedly attenuated the synaptic-plasticity-disrupting action of ADDLs. Indeed, despite the administration of ADDLs, HFS now induced robust LTP that was comparable to the control levels and which remained stable for more than 3 h (Exo + ADDL, 152 ± 6%, n = 5, P < 0.01 vs. PBS + ADDL; P > 0.4 vs. PBS + PBS, one-way ANOVA with post hoc Tukey; Figure 2A). Of note, the effect of exosomes against ADDL-induced LTP inhibition was largely dependent upon the amount of exosomes, producing a significant effect when 4 μg or more was infused (Figure 2B). Unless otherwise specified, therefore, we used 4 μg exosomes in the subsequent studies. In this condition, however, neither exosomes nor ADDLs significantly affected baseline synaptic transmission (Figure 2C). Exosomes might exert this protective effect by enhancing LTP per se, and/or functionally counteract the plasticity-disrupting effect of ADDLs. When we examined the ability of exosomes to convert decremental LTP into stable LTP or boost control LTP, however, we did not detect any significant difference on weak HFS-induced decremental LTP (PBS, 106 ± 7%, n = 5 vs. Exo, 117 ± 6%, n = 4, P > 0.3, unpaired t-test; Figure 2D) or standard HFS-induced LTP (PBS, 172 ± 13%, n = 5 vs. Exo, 175 ± 8%, n = 4, P > 0.8, unpaired t-test; Figure 2D). Thus, direct facilitatory effects on the magnitude of LTP are unlikely to account for the capability of exosomes to rapidly abrogate the inhibitory effects of ADDLs.


Exosomes neutralize synaptic-plasticity-disrupting activity of Aβ assemblies in vivo.

An K, Klyubin I, Kim Y, Jung JH, Mably AJ, O'Dowd ST, Lynch T, Kanmert D, Lemere CA, Finan GM, Park JW, Kim TW, Walsh DM, Rowan MJ, Kim JH - Mol Brain (2013)

Exosomes abrogate ADDL-mediated disruption of LTP. (A) Prior infusion of exosomes (4 μg in 5 μl, asterisk) prevented ADDLs (10 pmol in 5 μl, hash) inhibiting LTP. Animals received sequential injections of exosomes and ADDLs before the application of HFS (arrow). Insets show representative traces at the color-matched time points. Calibrations: 1.5 mV and 10 ms for all traces. (B) Dose-dependent protective effect of exosomes against ADDL-mediated disruption of LTP (0 μg Exo + ADDL, 100 ± 3%, n = 5; 0.2 μg Exo + ADDL, 105 ± 5%, n = 4; 1 μg Exo + ADDL, 123 ± 5%, n = 4; 4 μg Exo + ADDL, 151 ± 10%, n = 6; 10 μg Exo + ADDL, 168 ± 9%, n = 4). Statistical significance was expressed as **, P < 0.01 comparing to control group injected with 0 μg Exo + ADDL. (C) Neither exosomes nor ADDLs (5 μl, asterisk) affected baseline excitatory synaptic transmission in the CA1 area in vivo (PBS, n = 4; ADDL, n = 5; Exo, n = 4). (D) Exosomes (4 μg in 5 μl, asterisk) did not enhance decremental or standard LTP. An arrow indicates the time point of application of either weak HFS for decremental LTP or HFS for standard LTP, respectively. Insets and calibrations as in A. Error bars, ± SEM.
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Figure 2: Exosomes abrogate ADDL-mediated disruption of LTP. (A) Prior infusion of exosomes (4 μg in 5 μl, asterisk) prevented ADDLs (10 pmol in 5 μl, hash) inhibiting LTP. Animals received sequential injections of exosomes and ADDLs before the application of HFS (arrow). Insets show representative traces at the color-matched time points. Calibrations: 1.5 mV and 10 ms for all traces. (B) Dose-dependent protective effect of exosomes against ADDL-mediated disruption of LTP (0 μg Exo + ADDL, 100 ± 3%, n = 5; 0.2 μg Exo + ADDL, 105 ± 5%, n = 4; 1 μg Exo + ADDL, 123 ± 5%, n = 4; 4 μg Exo + ADDL, 151 ± 10%, n = 6; 10 μg Exo + ADDL, 168 ± 9%, n = 4). Statistical significance was expressed as **, P < 0.01 comparing to control group injected with 0 μg Exo + ADDL. (C) Neither exosomes nor ADDLs (5 μl, asterisk) affected baseline excitatory synaptic transmission in the CA1 area in vivo (PBS, n = 4; ADDL, n = 5; Exo, n = 4). (D) Exosomes (4 μg in 5 μl, asterisk) did not enhance decremental or standard LTP. An arrow indicates the time point of application of either weak HFS for decremental LTP or HFS for standard LTP, respectively. Insets and calibrations as in A. Error bars, ± SEM.
Mentions: In agreement with prior reports [5], high-frequency stimulation (HFS) failed to trigger robust LTP in anesthetized rats that had received i.c.v. injection of ADDLs (PBS + ADDL, 105 ± 6%, n = 4 vs. PBS + PBS, 166 ± 10%, n = 4 at 3 h post-HFS, P < 0.001, one-way ANOVA with post hoc Tukey; Figure 2A). Somewhat unexpectedly, prior infusion of 4 μg exosomes markedly attenuated the synaptic-plasticity-disrupting action of ADDLs. Indeed, despite the administration of ADDLs, HFS now induced robust LTP that was comparable to the control levels and which remained stable for more than 3 h (Exo + ADDL, 152 ± 6%, n = 5, P < 0.01 vs. PBS + ADDL; P > 0.4 vs. PBS + PBS, one-way ANOVA with post hoc Tukey; Figure 2A). Of note, the effect of exosomes against ADDL-induced LTP inhibition was largely dependent upon the amount of exosomes, producing a significant effect when 4 μg or more was infused (Figure 2B). Unless otherwise specified, therefore, we used 4 μg exosomes in the subsequent studies. In this condition, however, neither exosomes nor ADDLs significantly affected baseline synaptic transmission (Figure 2C). Exosomes might exert this protective effect by enhancing LTP per se, and/or functionally counteract the plasticity-disrupting effect of ADDLs. When we examined the ability of exosomes to convert decremental LTP into stable LTP or boost control LTP, however, we did not detect any significant difference on weak HFS-induced decremental LTP (PBS, 106 ± 7%, n = 5 vs. Exo, 117 ± 6%, n = 4, P > 0.3, unpaired t-test; Figure 2D) or standard HFS-induced LTP (PBS, 172 ± 13%, n = 5 vs. Exo, 175 ± 8%, n = 4, P > 0.8, unpaired t-test; Figure 2D). Thus, direct facilitatory effects on the magnitude of LTP are unlikely to account for the capability of exosomes to rapidly abrogate the inhibitory effects of ADDLs.

Bottom Line: We here provide in vivo evidence that exosomes derived from N2a cells or human cerebrospinal fluid can abrogate the synaptic-plasticity-disrupting activity of both synthetic and AD brain-derived Aβ.Mechanistically, this effect involves sequestration of synaptotoxic Aβ assemblies by exosomal surface proteins such as PrPC rather than Aβ proteolysis.These data suggest that exosomes can counteract the inhibitory action of Aβ, which contributes to perpetual capability for synaptic plasticity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Gyungbuk 790-784, Korea. joungkim@postech.ac.kr.

ABSTRACT

Background: Exosomes, small extracellular vesicles of endosomal origin, have been suggested to be involved in both the metabolism and aggregation of Alzheimer's disease (AD)-associated amyloid β-protein (Aβ). Despite their ubiquitous presence and the inclusion of components which can potentially interact with Aβ, the role of exosomes in regulating synaptic dysfunction induced by Aβ has not been explored.

Results: We here provide in vivo evidence that exosomes derived from N2a cells or human cerebrospinal fluid can abrogate the synaptic-plasticity-disrupting activity of both synthetic and AD brain-derived Aβ. Mechanistically, this effect involves sequestration of synaptotoxic Aβ assemblies by exosomal surface proteins such as PrPC rather than Aβ proteolysis.

Conclusions: These data suggest that exosomes can counteract the inhibitory action of Aβ, which contributes to perpetual capability for synaptic plasticity.

Show MeSH
Related in: MedlinePlus