TREK1 upregulation is an endogenous mechanism delaying cognitive decline in Alzheimer's Disease

Alzheimers Disease (AD) is marked by early hippocampal and neocortical accumulation of amyloid-beta 42 oligomers (A{beta}42o), driving neuronal hyperactivity and synaptic dysfunction years before symptom onset. While two-pore domain leak potassium channels like TREK1 are crucial for maintaining the resting membrane potential of neurons and shaping their excitability profile, their role in major neurodegenerative disorders like 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 A{beta}42o -induced hyperactivity. Mechanistically, we show that increased intracellular calcium activates adenylate cyclase 1/8 (AC1/8), initiating a cAMP-PKA signaling 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. Through a combination of calcium imaging, patch-clamp electrophysiology, immunostaining, and cognitive assays in a hippocampal TREK1 knockdown AD model, we establish that the pathology-associated upregulation of TREK1 constitutes a critical homeostatic brake on neuronal hyperexcitability. This neuronal response is essential for limiting A{beta}42o-mediated synaptic pathology and delaying cognitive decline. Our study identifies a multi-step signaling cascade triggered by A{beta}42o leading to upregulation of TREK1 that functions as an essential compensatory mechanism for neuronal survival in early AD. This study deciphers a cellular mechanism responsible for the preclinical phase of AD characterized by silent buildup of pathology.