Synaptic dysregulation and hyperexcitability induced by intracellular amyloid beta oligomers

Fernández-Pérez, Eduardo J.; Muñoz, Braulio; Bascuñán, Denisse; Peters, Christian; Riffo-Lepe, Nicolas Osiel; Espinoza, María Paz; Morgan, Peter James; Filippi, Caroline; Bourboulou, Romain; Sengupta, Urmi; Kayed, Rakez; Epsztein, Jérôme; Aguayo, Luis G.

doi:10.1111/acel.13455

Cited by 22 publications

(13 citation statements)

References 139 publications

(186 reference statements)

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“…Our results also suggest that changes in neuronal excitability might be occurring during the postsynaptic recordings, as evidenced by the higher number of recorded voltageclamped spikes as the concentration of αSynO increased. In fact, the effects described for intracellular αSynO regarding the frequency, amplitude, charge transferred, and increased number of voltage-clamped recorded spikes in the recordings are remarkably similar to those described for intracellular Aβ oligomers (Aβo) in a previous study by our laboratory [52]. Contrary to our findings, Yamamoto et al reported that the intracellular diffusion of a solution containing stable higher-order αSynO (larger than 100 kDa) decreased neuronal excitability [16].…”

Section: Intracellular Effects Of αSyno In Synaptic Physiologysupporting

confidence: 89%

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The Stimulatory Effects of Intracellular α-Synuclein on Synaptic Transmission Are Attenuated by 2-Octahydroisoquinolin-2(1H)-ylethanamine

Ramírez

Fernández-Pérez

Olivos

et al. 2021

IJMS

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α-Synuclein (αSyn) species can be detected in synaptic boutons, where they play a crucial role in the pathogenesis of Parkinson’s Disease (PD). However, the effects of intracellular αSyn species on synaptic transmission have not been thoroughly studied. Here, using patch-clamp recordings in hippocampal neurons, we report that αSyn oligomers (αSynO), intracellularly delivered through the patch electrode, produced a fast and potent effect on synaptic transmission, causing a substantial increase in the frequency, amplitude and transferred charge of spontaneous synaptic currents. We also found an increase in the frequency of miniature synaptic currents, suggesting an effect located at the presynaptic site of the synapsis. Furthermore, our in silico approximation using docking analysis and molecular dynamics simulations showed an interaction between a previously described small anti-amyloid beta (Aβ) molecule, termed M30 (2-octahydroisoquinolin-2(1H)-ylethanamine), with a central hydrophobic region of αSyn. In line with this finding, our empirical data aimed to obtain oligomerization states with thioflavin T (ThT) and Western blot (WB) indicated that M30 interfered with αSyn aggregation and decreased the formation of higher-molecular-weight species. Furthermore, the effect of αSynO on synaptic physiology was also antagonized by M30, resulting in a decrease in the frequency, amplitude, and charge transferred of synaptic currents. Overall, the present results show an excitatory effect of intracellular αSyn low molecular-weight species, not previously described, that are able to affect synaptic transmission, and the potential of a small neuroactive molecule to interfere with the aggregation process and the synaptic effect of αSyn, suggesting that M30 could be a potential therapeutic strategy for synucleinopathies.

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Section: Intracellular Effects Of αSyno In Synaptic Physiologysupporting

confidence: 89%

“…The synaptic currents were analyzed as previously described [52]. Briefly, miniature postsynaptic current (mPSCs) frequency and amplitude were analyzed using the Mini analysis software (Synaptosoft, Inc., Leonia, NJ, USA).…”

Section: Data Analysis and Statisticsmentioning

confidence: 99%

The Stimulatory Effects of Intracellular α-Synuclein on Synaptic Transmission Are Attenuated by 2-Octahydroisoquinolin-2(1H)-ylethanamine

Ramírez

Fernández-Pérez

Olivos

et al. 2021

IJMS

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“…APP transgenic mice evidently reveal deficits in learning and memory, behavioral abnormalities, synaptic alterations, and SPs [ 25 ]. Intracellular Aβ oligomers can affect normal transmission, increase neuronal excitability of hippocampal neurons, and cause synaptic damage [ 26 ]. Mitochondria-associated membranes are an intracellular site of APP processing and Aβ is produced at mitochondria-endoplasmic reticulum contact sites, which may contribute to AD pathology [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Anti-Inflammatory Activity of 4-(4-(Heptyloxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one via Repression of MAPK/NF-κB Signaling Pathways in β-Amyloid-Induced Alzheimer’s Disease Models

Xuan

Liu

et al. 2022

Molecules

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Alzheimer’s disease (AD) is a major neurodegenerative disease, but so far, it can only be treated symptomatically rather than changing the process of the disease. Recently, triazoles and their derivatives have been shown to have potential for the treatment of AD. In this study, the neuroprotective effects of 4-(4-(heptyloxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (W112) against β-amyloid (Aβ)-induced AD pathology and its possible mechanism were explored both in vitro and in vivo. The results showed that W112 exhibits a neuroprotective role against Aβ-induced cytotoxicity in PC12 cells and improves the learning and memory abilities of Aβ-induced AD-like rats. In addition, the assays of the protein expression revealed that W112 reversed tau hyperphosphorylation and reduced the production of proinflammatory cytokines, tumor necrosis factor-α and interleukin-6, both in vitro and in vivo studies. Further study indicated that the regulation of mitogen-activated protein kinase/nuclear factor-κB pathways played a key role in mediating the neuroprotective effects of W112 against AD-like pathology. W112 may become a potential drug for AD intervention.

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“…Moreover, the actions of Aβ on synapses are reportedly mediated by PKCα through scaffold interactions (Alfonso et al, 2016 ). In the initial stages of AD, accumulated intracellular amyloid-beta oligomer causes functional spreading of hyperexcitability through a synaptic-driven mechanism, which is PKC-dependent (Fernandez-Perez et al, 2021 ). Significant suppression of PKCα activity was observed in the wild-type and 3×Tg-AD mice in the aged or postsurgical hippocampus.…”

Section: Discussionmentioning

confidence: 99%

The role of PKC/PKR in aging, Alzheimer's disease, and perioperative neurocognitive disorders

Lü

Tang

et al. 2022

Front. Aging Neurosci.

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BackgroundThe incidence of perioperative neurocognitive disorders (PNDs) is reportedly higher in older patients. Mitochondrial and synaptic dysfunctions have consistently been demonstrated in models of aging and neurodegenerative diseases; nonetheless, their role in PND is not well understood.MethodsThe Morris water maze and elevated plus maze tests were used to assess the learning and memory abilities of both C57BL/6 and 3×Tg-AD mice of different ages (8 and 18 months). PND was induced by laparotomy in C57BL/6 mice and 3×Tg-AD mice (8 months old). Markers associated with neuroinflammation, mitochondrial function, synaptic function, and autophagy were assessed postoperatively. The roles of protein kinase C (PKC) and double-stranded RNA-dependent protein kinase (PKR) were further demonstrated by using PKC-sensitive inhibitor bisindolylmaleimide X (BIMX) or PKR−/− mice.ResultsSignificant cognitive impairment was accompanied by mitochondrial dysfunction and autophagy inactivation in both aged C57BL/6 and 3×Tg-AD mice. Laparotomy induced a significant neuroinflammatory response and synaptic protein loss in the hippocampus. Cognitive and neuropathological changes induced by aging or laparotomy were further exacerbated in 3×Tg-AD mice. Deficits in postoperative cognition, hippocampal mitochondria, autophagy, and synapse were significantly attenuated after pharmacological inhibition of PKC or genetic deletion of PKR.ConclusionsOur findings suggest similar pathogenic features in aging, Alzheimer's disease, and PND, including altered mitochondrial homeostasis and autophagy dysregulation. In addition, laparotomy may exacerbate cognitive deficits associated with distinct neuronal inflammation, mitochondrial dysfunction, and neuronal loss independent of genetic background. The dysregulation of PKC/PKR activity may participate in the pathogenesis of these neurodegenerative diseases.

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Synaptic dysregulation and hyperexcitability induced by intracellular amyloid beta oligomers

Abstract: This is an open access article under the terms of the Creative Commons AttributionLicense, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 22 publications

References 139 publications

The Stimulatory Effects of Intracellular α-Synuclein on Synaptic Transmission Are Attenuated by 2-Octahydroisoquinolin-2(1H)-ylethanamine

The Stimulatory Effects of Intracellular α-Synuclein on Synaptic Transmission Are Attenuated by 2-Octahydroisoquinolin-2(1H)-ylethanamine

Anti-Inflammatory Activity of 4-(4-(Heptyloxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one via Repression of MAPK/NF-κB Signaling Pathways in β-Amyloid-Induced Alzheimer’s Disease Models

The role of PKC/PKR in aging, Alzheimer's disease, and perioperative neurocognitive disorders

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