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Reciprocal structure–function relationships underlie both healthy and pathological behaviours in complex neural networks. Thus, understanding neuropathology and network dysfunction requires a thorough investigation of the complex interactions between structural and functional network reconfigurations in response to perturbation. Such adaptations are often difficult to study in vivo. For example, subtle, evolving changes in synaptic connectivity, transmission and the electrophysiological shift from healthy to pathological states, for example alterations that may be associated with evolving neurodegenerative disease, such as Alzheimer's, are difficult to study in the brain. Engineered in vitro neural networks are powerful models that enable selective targeting, manipulation and monitoring of dynamic neural network behaviour at the micro- and mesoscale in physiological and pathological conditions. In this study, we engineered feedforward cortical neural networks using two-nodal microfluidic devices with controllable connectivity interfaced with microelectrode arrays (mMEAs). We induced P301L mutated tau protein to the presynaptic node of these networks and monitored network dynamics over three weeks. Induced perturbation resulted in altered structural organization and extensive axonal retraction starting in the perturbed node. Perturbed networks also exhibited functional changes in intranodal activity, which manifested as an overall decline in both firing rate and bursting activity, with a progressive increase in synchrony over time and a decrease in internodal signal propagation between pre- and post-synaptic nodes. These results provide insights into dynamic structural and functional reconfigurations at the micro- and mesoscale as a result of evolving pathology and illustrate the utility of engineered networks as models of network function and dysfunction.