nctions have been described, the molecular or structural reasons

nctions have been described, the molecular or structural reasons underlying distant break down of specific networks and the relationship between amyloid and Tau pathology are still unclear. Recent advances in the development of microfluidic devices facilitate microenvironment development adapted to neuronal structures and subdomains with easy access and control. We have previously designed and developed a uFD system to polarize neuronal networks using funnel shaped micro channels, also called a onal diodes, allowing the reconstruction of an orientated functional cortico striatal neuronal network in vitro. In the present study, we used a similar uFD based approach to study the molecular mechanism of neurodegenerative processes in compartmentalized neurons and neuronal networks.

By compartmentalizing a on terminals from cell bodies of cortical neurons, we demonstrate that a ons are partially resistant to a onal AB peptide e posure, while somatic treatments trigger an anterograde degeneration signal in a ons, inducing Inhibitors,Modulators,Libraries a dying back pattern. We then reconstructed an oriented cortico hippocampal network in uFD, and showed that somato dendritic deposits Inhibitors,Modulators,Libraries of AB on cortical neurons trigger a rapid cortical presynaptic disconnection concomitant with a glutamate dependent Inhibitors,Modulators,Libraries postsynaptic hippocampal tau phosphorylation before any a onal and somatic cortical degeneration. Results Somato dendritic e posure of cortical neurons to AB Inhibitors,Modulators,Libraries peptide induces an a onal dying back pattern We wondered whether localized B amyloid deposition on different subcellular compartments lead to local degenerative signals or to a global neuronal degeneration.

A ons were compartmentalized from the somato dendritic compartment by seeding cortical neurons in uFD devices comprising two cham bers connected through asymmetrical micro channels. When seeded in the left chamber, cortical neurons projected their a ons from the somato dendritic Cilengitide compartment to the distal compartment through filter ing micro channels. Analysis of den drites and nuclear chromatin visualization indicated that the seeded cortical neurons were healthy after two weeks in culture. Somato dendritic application of fibrillar AB25 35, mimicking amyloid plaques, induced a onal degeneration process. While somato dentritic application of aggregated AB did not affect somatic and dendritic viability some local synaptic damage was evidenced in the som atic chamber.

Addition of NAD, pharmacological inhibitors of c Jun N terminal kinases, or caspases inhibitor, to the a onal compartment signifi such cantly reduced AB induced a onal degeneration. In contrast, distal a onal application of aggregated AB failed to induce any significant a onal degeneration in our paradigm. Interestingly, while low dose of somato dendritic glutamate treatment did not trigger a onal degeneration per se, the combination of distal AB application with this sub to ic dose of glutamate to the somato dendritic compartment triggered a massive a onal fragmentation. This

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