β-amyloid induces a dying-back process and remote trans-synaptic alterations in a microfluidic-based reconstructed...

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Neurodegenerative diseases like Alzheimer's and Parkinson's involve pathological hallmarks spreading along neuronal networks.
• Understanding the molecular mechanisms of this trans-synaptic propagation is challenging due to brain complexity.
• Novel experimental models are needed to manipulate local microenvironments at the subcellular level.

Purpose of the Study:

• To investigate the effects of local amyloid-beta (Aβ) application on different neuronal compartments using microfluidic devices.
• To study the impact of subcellular Aβ stress on neuronal networks and identify early pathological events.
• To explore the relationship between local Aβ deposition and remote tau pathology.

Main Methods:

• Primary cortical mouse neurons were cultured in microfluidic (μFD) devices to isolate somato-dendritic and axonal compartments.
• Amyloid-beta (Aβ) peptides were applied locally to distinct cellular compartments.
• μFD multi-chamber devices with unidirectional axon growth channels recreated in vitro cortico-hippocampal pathways.
• Effects on neuronal degeneration, caspase and NAD(+) signaling, and tau phosphorylation were analyzed.

Main Results:

• Local Aβ application to the somato-dendritic compartment induced a "dying-back" degeneration involving caspase and NAD(+) pathways.
• Axonal Aβ exposure alone did not cause degeneration, but co-treatment with glutamate did.
• Aβ application to cortical neurons caused rapid pre-synaptic loss and subsequent hippocampal post-synaptic tau phosphorylation.
• NMDA-receptor antagonist MK-801 prevented tau phosphorylation before overt cellular damage.

Conclusions:

• Microfluidic devices enable the study of distant effects of local Aβ stress on neuronal networks.
• Distal neurotransmission alterations, independent of local Aβ production, contribute to early pathology progression.
• Local Aβ can induce remote tauopathy through disturbed neurotransmission, explaining the spatiotemporal spread of pathology.