Cortical somato dendritic B amyloid peptide e posure induces a rapid disconnection of cortico hippocampal synapses, which precedes a onal degeneration To decipher whether local AB might induce remote now to ic effect on synapses we used 2C uFD a onal diodes chips that allows reconstructing oriented neuronal networks, to create a unidirectional cortico hippocampal network. When primary cortical neurons were cultured at high density in the left chamber of the device and hippocampal neurons were seeded at low density in the right chamber, cortical neurons projected a ons through the funnel shaped micro channels and established synapses with hippocampal neurons in the right chamber. Thanks to the funnel shaped u channels, hippocampal neurons did not project a ons backwards.

While hippocampal neurons cultured alone showed few presynaptic cluster along their dendritic shaft, Hippocampal neurons grown in contact recognizing the phospho threonine 231 epitope detects one of the earliest phosphorylation changes observed in AD patients. After 24 h of AB treatment in the C chamber we found that phosphorylation levels of Tau Thr231 increased in post synaptic hippocampal neurons. Tau Thr231 phosphorylation was particularly concentrated in the cell bodies and pro imal dendrites of hippocampal neurons, rather than in distal dendrites and a ons. This effect appeared to be glutamate dependent as phosphoryl ation was prevented by hippocampal pre treatment with the NMDA receptor antagonist, MK801.

Hence, AB mediated disturbance of glutamatergic neurotrans mission and concomitant Dacomitinib synapse loss can induce Tau phosphorylation in connected hippocampal neurons and subsequently a onal degeneration of cortical fibers, with cortical fibers showed high density presynaptic clusters as evidenced by dense synuclein or VGLUT1 staining along the hippocampal dendrites. Application of AB25 35 peptide to the C compart ment induced cortico hippocampal synapse loss in the Hi compartment within 24 h, whereas cortical a ons and soma showed no obvious sign of de generation. Similar results were obtained with nanomolar doses of oligomeric or fibrillar AB1 42 suggesting that this process does not rely on the aggregation state of the peptides. While cortical fibers were still intact 24 h after AB appli cation, at 48 h after treatment, connected a ons started to degenerate. We thus observed that the first structural alteration following somato dendritic AB deposits is a distant synapse loss that is followed by delayed a onal degeneration, reminiscent of a dying back process.