ß-amyloid induces a dying-back process and remote trans-synaptic alterations in a microfluidic-based reconstructed neuronal network

Deleglise, Bérangère; Magnifico, Sébastien; Duplus, Eric; Vaur, Pauline; Soubeyre, Vanessa; Belle, Morgane; Vignes, Maéva; Viovy, Jean‐Louis; Jacotot, Étienne; Peyrin, Jean-Michel; Brugg, Bernard

doi:10.1186/preaccept-4848873741397798

Cited by 13 publications

(19 citation statements)

References 12 publications

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“…A surprising observation was that upon axonal rotenone insults in low glucose conditions, although the treated axonal segments degenerate through a caspase-dependent pathway13, no significant retrograde spreading toward the cell body was evidenced in basal conditions. Interestingly, while our previous observations suggested that axons have high intrinsic resistance toward direct apoptosis activation1365, a recent report showed that direct axonal apoptotic degeneration is gated by a somatic apoptotic signaling19. Collectively these findings support the notion that unchallenged parts of the neurons may buffer the spreading of toxic signals in the cytoplasm as previously hypothesized66 and suggested by experimental results showing that locally induced mitochondrial damages in vivo are due to a local and reversible process39.…”

Section: Discussionsupporting

confidence: 78%

Alterations of mitochondrial dynamics allow retrograde propagation of locally initiated axonal insults

Lassus

Magifico

Pignon

et al. 2016

Sci Rep

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In chronic neurodegenerative syndromes, neurons progressively die through a generalized retraction pattern triggering retrograde axonal degeneration toward the cell bodies, which molecular mechanisms remain elusive. Recent observations suggest that direct activation of pro-apoptotic signaling in axons triggers local degenerative events associated with early alteration of axonal mitochondrial dynamics. This raises the question of the role of mitochondrial dynamics on both axonal vulnerability stress and their implication in the spreading of damages toward unchallenged parts of the neuron. Here, using microfluidic chambers, we assessed the consequences of interfering with OPA1 and DRP1 proteins on axonal degeneration induced by local application of rotenone. We found that pharmacological inhibition of mitochondrial fission prevented axonal damage induced by rotenone, in low glucose conditions. While alteration of mitochondrial dynamics per se did not lead to spontaneous axonal degeneration, it dramatically enhanced axonal vulnerability to rotenone, which had no effect in normal glucose conditions, and promoted retrograde spreading of axonal degeneration toward the cell body. Altogether, our results suggest a mitochondrial priming effect in axons as a key process of axonal degeneration. In the context of neurodegenerative diseases, like Parkinson’s and Alzheimer’s, mitochondria fragmentation could hasten neuronal death and initiate spatial dispersion of locally induced degenerative events.

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Section: Discussionsupporting

confidence: 78%

Alterations of mitochondrial dynamics allow retrograde propagation of locally initiated axonal insults

Lassus

Magifico

Pignon

et al. 2016

Sci Rep

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“…Axonal degeneration following neuronal insults, such as toxins, metabolic disturbances, infections and mutations growth, occurs in a process called ‘dying-back’ that starts distally and then spreads toward the cell body; 30 this phenomenon was also found in neurodegenerative diseases including Alzheimer’s and Parkinson’s diseases over weeks or months. 31, 32 Although there is no report establishing that dendrite degeneration occurs by a dying-back process, the present study provides a clue that chronic brain ischemia may induce a dying-back process of dendrite degeneration. However, more evidence is needed to clarify this process as well as the potential molecular mechanism.…”

Section: Discussionmentioning

confidence: 57%

MicroRNA-195 prevents dendritic degeneration and neuron death in rats following chronic brain hypoperfusion

et al. 2017

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Impaired synaptic plasticity and neuron loss are hallmarks of Alzheimer’s disease and vascular dementia. Here, we found that chronic brain hypoperfusion (CBH) by bilateral common carotid artery occlusion (2VO) decreased the total length, numbers and crossings of dendrites and caused neuron death in rat hippocampi and cortices. It also led to increase in N-terminal β-amyloid precursor protein (N-APP) and death receptor-6 (DR6) protein levels and in the activation of caspase-3 and caspase-6. Further study showed that DR6 protein was downregulated by miR-195 overexpression, upregulated by miR-195 inhibition, and unchanged by binding-site mutation and miR-masks. Knockdown of endogenous miR-195 by lentiviral vector-mediated overexpression of its antisense molecule (lenti-pre-AMO-miR-195) decreased the total length, numbers and crossings of dendrites and neuron death, upregulated N-APP and DR6 levels, and elevated cleaved caspase-3 and caspase-6 levels. Overexpression of miR-195 using lenti-pre-miR-195 prevented these changes triggered by 2VO. We conclude that miR-195 is involved in CBH-induced dendritic degeneration and neuron death through activation of the N-APP/DR6/caspase pathway.

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“…To extend our study to mature neurons, we combined the use of primary cultures of mouse cerebellar granule neurons (CGNs) and of a reconstructed cortico-striatal neuronal network grown on microfluidic chips [ 34 – 36 ]. CGNs are helpful to probe the effect of prion infection on the axon and dendrites [ 37 , 38 ].…”

Section: Resultsmentioning

confidence: 99%

Double-Edge Sword of Sustained ROCK Activation in Prion Diseases through Neuritogenesis Defects and Prion Accumulation

et al. 2015

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In prion diseases, synapse dysfunction, axon retraction and loss of neuronal polarity precede neuronal death. The mechanisms driving such polarization defects, however, remain unclear. Here, we examined the contribution of RhoA-associated coiled-coil containing kinases (ROCK), key players in neuritogenesis, to prion diseases. We found that overactivation of ROCK signaling occurred in neuronal stem cells infected by pathogenic prions (PrPSc) and impaired the sprouting of neurites. In reconstructed networks of mature neurons, PrPSc-induced ROCK overactivation provoked synapse disconnection and dendrite/axon degeneration. This overactivation of ROCK also disturbed overall neurotransmitter-associated functions. Importantly, we demonstrated that beyond its impact on neuronal polarity ROCK overactivity favored the production of PrPSc through a ROCK-dependent control of 3-phosphoinositide-dependent kinase 1 (PDK1) activity. In non-infectious conditions, ROCK and PDK1 associated within a complex and ROCK phosphorylated PDK1, conferring basal activity to PDK1. In prion-infected neurons, exacerbated ROCK activity increased the pool of PDK1 molecules physically interacting with and phosphorylated by ROCK. ROCK-induced PDK1 overstimulation then canceled the neuroprotective α-cleavage of normal cellular prion protein PrPC by TACE α-secretase, which physiologically precludes PrPSc production. In prion-infected cells, inhibition of ROCK rescued neurite sprouting, preserved neuronal architecture, restored neuronal functions and reduced the amount of PrPSc. In mice challenged with prions, inhibition of ROCK also lowered brain PrPSc accumulation, reduced motor impairment and extended survival. We conclude that ROCK overactivation exerts a double detrimental effect in prion diseases by altering neuronal polarity and triggering PrPSc accumulation. Eventually ROCK emerges as therapeutic target to combat prion diseases.

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ß-amyloid induces a dying-back process and remote trans-synaptic alterations in a microfluidic-based reconstructed neuronal network

Cited by 13 publications

References 12 publications

Alterations of mitochondrial dynamics allow retrograde propagation of locally initiated axonal insults

Alterations of mitochondrial dynamics allow retrograde propagation of locally initiated axonal insults

MicroRNA-195 prevents dendritic degeneration and neuron death in rats following chronic brain hypoperfusion

Double-Edge Sword of Sustained ROCK Activation in Prion Diseases through Neuritogenesis Defects and Prion Accumulation

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