Alpha-synuclein oligomers impair memory through glial cell activation and via Toll-like receptor 2

Pietro La Vitola, Claudia Balducci, Milica Cerovic, Giulia Santamaria, Edoardo Brandi, Federica Grandi, Laura Caldinelli, Laura Colombo, Maria Grazia Morgese, Luigia Trabace, Loredano Pollegioni, Diego Albani, Gianluigi Forloni

Research output: Contribution to journalArticle

Abstract

Alpha-synuclein oligomers (α-synOs) are emerging as crucial factors in the pathogenesis of synucleinopathies. Although the connection between neuroinflammation and α-syn still remains elusive, increasing evidence suggests that extracellular moieties activate glial cells leading to neuronal damage. Using an acute mouse model, we explored whether α-synOs induce memory impairment in association to neuroinflammation, addressing Toll-like receptors 2 and 4 (TLR2 and TLR4) involvement. We found that α-synOs abolished mouse memory establishment in association to hippocampal glial activation. On brain slices α-synOs inhibited long-term potentiation. Indomethacin and Ibuprofen prevented the α-synOs-mediated detrimental actions. Furthermore, while the TLR2 functional inhibitor antibody prevented the memory deficit, oligomers induced memory deficits in the TLR4 knockout mice. In conclusion, solely α-synOs induce memory impairment likely inhibiting synaptic plasticity. α-synOs lead to hippocampal gliosis that is involved in memory impairment. Moreover, while the oligomer-mediated detrimental actions are TLR2 dependent, the involvement of TLR4 was ruled out.

Original languageEnglish
Pages (from-to)591-602
Number of pages12
JournalBrain, Behavior, and Immunity
Volume69
DOIs
Publication statusPublished - Mar 2018

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Toll-Like Receptor 2
alpha-Synuclein
Neuroglia
Memory Disorders
Toll-Like Receptor 4
Neuronal Plasticity
Gliosis
Long-Term Potentiation
Ibuprofen
Knockout Mice
Indomethacin
Antibodies
Brain

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Alpha-synuclein oligomers impair memory through glial cell activation and via Toll-like receptor 2. / La Vitola, Pietro; Balducci, Claudia; Cerovic, Milica; Santamaria, Giulia; Brandi, Edoardo; Grandi, Federica; Caldinelli, Laura; Colombo, Laura; Morgese, Maria Grazia; Trabace, Luigia; Pollegioni, Loredano; Albani, Diego; Forloni, Gianluigi.

In: Brain, Behavior, and Immunity, Vol. 69, 03.2018, p. 591-602.

Research output: Contribution to journalArticle

La Vitola, Pietro ; Balducci, Claudia ; Cerovic, Milica ; Santamaria, Giulia ; Brandi, Edoardo ; Grandi, Federica ; Caldinelli, Laura ; Colombo, Laura ; Morgese, Maria Grazia ; Trabace, Luigia ; Pollegioni, Loredano ; Albani, Diego ; Forloni, Gianluigi. / Alpha-synuclein oligomers impair memory through glial cell activation and via Toll-like receptor 2. In: Brain, Behavior, and Immunity. 2018 ; Vol. 69. pp. 591-602.
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AU - Balducci, Claudia

AU - Cerovic, Milica

AU - Santamaria, Giulia

AU - Brandi, Edoardo

AU - Grandi, Federica

AU - Caldinelli, Laura

AU - Colombo, Laura

AU - Morgese, Maria Grazia

AU - Trabace, Luigia

AU - Pollegioni, Loredano

AU - Albani, Diego

AU - Forloni, Gianluigi

N1 - Copyright © 2018 Elsevier Inc. All rights reserved.

PY - 2018/3

Y1 - 2018/3

N2 - Alpha-synuclein oligomers (α-synOs) are emerging as crucial factors in the pathogenesis of synucleinopathies. Although the connection between neuroinflammation and α-syn still remains elusive, increasing evidence suggests that extracellular moieties activate glial cells leading to neuronal damage. Using an acute mouse model, we explored whether α-synOs induce memory impairment in association to neuroinflammation, addressing Toll-like receptors 2 and 4 (TLR2 and TLR4) involvement. We found that α-synOs abolished mouse memory establishment in association to hippocampal glial activation. On brain slices α-synOs inhibited long-term potentiation. Indomethacin and Ibuprofen prevented the α-synOs-mediated detrimental actions. Furthermore, while the TLR2 functional inhibitor antibody prevented the memory deficit, oligomers induced memory deficits in the TLR4 knockout mice. In conclusion, solely α-synOs induce memory impairment likely inhibiting synaptic plasticity. α-synOs lead to hippocampal gliosis that is involved in memory impairment. Moreover, while the oligomer-mediated detrimental actions are TLR2 dependent, the involvement of TLR4 was ruled out.

AB - Alpha-synuclein oligomers (α-synOs) are emerging as crucial factors in the pathogenesis of synucleinopathies. Although the connection between neuroinflammation and α-syn still remains elusive, increasing evidence suggests that extracellular moieties activate glial cells leading to neuronal damage. Using an acute mouse model, we explored whether α-synOs induce memory impairment in association to neuroinflammation, addressing Toll-like receptors 2 and 4 (TLR2 and TLR4) involvement. We found that α-synOs abolished mouse memory establishment in association to hippocampal glial activation. On brain slices α-synOs inhibited long-term potentiation. Indomethacin and Ibuprofen prevented the α-synOs-mediated detrimental actions. Furthermore, while the TLR2 functional inhibitor antibody prevented the memory deficit, oligomers induced memory deficits in the TLR4 knockout mice. In conclusion, solely α-synOs induce memory impairment likely inhibiting synaptic plasticity. α-synOs lead to hippocampal gliosis that is involved in memory impairment. Moreover, while the oligomer-mediated detrimental actions are TLR2 dependent, the involvement of TLR4 was ruled out.

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DO - 10.1016/j.bbi.2018.02.012

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