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Researchers used human iPSC-derived neurons to investigate how the familial MAPT P301L tau mutation causes neuronal network dysfunction in Alzheimer's disease and related tauopathies. They discovered that this mutation creates hyperexcitability in neuronal networks by differentially affecting excitatory and inhibitory neurons through distinct tau protein interactions in each cell type. The study demonstrated that network function could be restored either by reducing excitatory synaptic transmission or by blocking calcium influx specifically in inhibitory neurons where tau interacts with the AHNAK protein.
Why it matters
This research identifies specific cellular mechanisms underlying network dysfunction in tauopathies, potentially revealing new therapeutic targets for Alzheimer's disease and related disorders. The findings suggest that treatments could focus on correcting the excitatory-inhibitory imbalance rather than solely targeting tau aggregation.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Pathological tau disrupts neuronal activity and brain function in Alzheimer s disease and other tauopathies. However, the underlying mechanisms for neuronal network dysfunction remain largely unknown. Using human inducible pluripotent stem cell (iPSC) – derived neurons, we show that the familial MAPT P301L mutation leads to neuronal network hyperexcitability. Imbalanced excitation and inhibition were attributable to neuronal subtype-specific tau pathology that was associated with different alterations of tau interactomes in excitatory versus inhibitory neurons. Suppressing enhanced excitatory synaptic transmission or blocking Ca2+ influx resulting from enhanced P301L tau/AHNAK interaction in inhibitory neurons rescued the neuronal network hyperexcitability. This study expands our understanding on how disease-causing tau mutations alter the excitatory/inhibitory balance, leading to network dysfunction in human neurons.