Hyperexcitability in Alzheimer’s Disease triggers a compensatory neuroprotective response via TREK1

Alzheimer’s Disease (AD) is marked by early hippocampal and neocortical accumulation of amyloid-beta 42 oligomers (Aβ42o), driving neuronal hyperactivity and synaptic dysfunction years before symptom onset. While two-pore domain leak potassium channels like TREK1 provide neuroprotection against hyperexcitability, their role in AD remains unknown. Here, we discover an activity-dependent upregulation of TREK1 in AD transgenic mice (3xTg and APP/PS1) and cultured hippocampal/cortical neurons, triggered by Aβ42o -induced hyperactivity.

Mechanistically, we show that increased intracellular calcium activates adenylate cyclase 1/8 (AC1/8), initiating a cAMP-PKA signalling cascade that enhances the expression of chromatin regulator CTCF. This increased CTCF in turn enhances the expression of TREK1 both in vitro and in AD transgenic mice. Using calcium imaging, patch clamp electrophysiology, immunohistochemistry assays, we demonstrate that the upregulation of TREK1 serves as a critical brake on neuronal hyperexcitability and is essential for restoring synaptic balance and mitigating AD pathology. Our study identifies a multi-step signalling cascade triggered by Aβ42o leading to upregulation of TREK1 that functions as an essential compensatory mechanism for neuronal survival in early AD.