Electrophysiological markers of network communication in an Alzheimer’s disease mouse model with early tau pathology

The aggregation of misfolded tau protein in the brain is a critical step in the development of neurodegenerative tauopathies, such as Alzheimer’s disease and frontotemporal dementias. The extent and severity of tau pathology correlate with cognitive decline, but the cellular and network mediators of memory consolidation deficits have not yet been elucidated. Tauopathy mouse models have historically exhibited rapid, non-physiological and widespread transgenic overexpression of mutant tau, and so the network effects of early and localised tau pathology that exists at disease onset remain largely unexplored. We employed a novel tau mouse model, the MAPTS305N; Int10+3 knock in (MAPT KI) line, to investigate the earliest stages of tau pathology, capturing electrophysiological changes using concurrent Neuropixels recordings across distributed brain regions, over the course of tau pathology progression. Electrophysiological deficits became more pronounced with age and pathological advancement. The entorhinal cortex and hippocampal CA1 exhibited increased neuronal firing across behavioural states, in contrast to previous observations in transgenic models. Sleep macrostructure was also disordered, showing an increase in REM sleep and fragmentation of nREM sleep. During nREM sleep, oscillatory events involved in coordinating multiple brain regions for memory consolidation were impaired in older MAPT KI mice. Specifically, spiking responses to sleep spindles, and the temporal coordination of spindles to hippocampal ripples and cortical delta waves became dysregulated in older MAPT KI mice. Finally, a novel intervention to degrade tau aggregates was administered to MAPT KI mice and successfully reduced synaptic tau to WT levels. This work characterises the early network effects of tau pathology, revealing deficits in processes integral to memory consolidation. These findings may provide novel targets for the direct treatment of network dysfunction in tauopathies. Additionally, these circuit deficits may be detectable in patients, and represent novel potential biomarkers for the early detection and diagnosis of tau-related neurodegenerative disease.Electrophysiological deficits became more pronounced with age and pathological advancement. The entorhinal cortex and hippocampal CA1 exhibited increased neuronal firing across behavioural states, in contrast to previous observations in transgenic models. Sleep macrostructure was also disordered, showing an increase in REM sleep and fragmentation of nREM sleep. During nREM sleep, oscillatory events involved in coordinating multiple brain regions for memory consolidation were impaired in older MAPT KI mice. Specifically, spiking responses to sleep spindles, and the temporal coordination of spindles to hippocampal ripples and cortical delta waves became dysregulated in older MAPT KI mice. Finally, a novel intervention to degrade tau aggregates was administered to MAPT KI mice and successfully reduced synaptic tau to WT levels.[GU2.1] This work characterises the early network effects of tau pathology, revealing deficits in processes integral to memory consolidation. These findings may provide novel targets for the direct treatment of network dysfunction in tauopathies[GU3.1]. Additionally, these circuit deficits may be detectable in patients, and represent novel potential biomarkers for the early detection and diagnosis of tau-related neurodegenerative disease.