Restoring neuronal chloride extrusion reverses cognitive decline linked to Alzheimer's disease mutations.
Iason KeramidisBrendan B McAllisterJulien BourbonnaisFeng WangDominique IsabelEdris RezaeiRomain SansonettiPhil DegagneJustin P HamelMojtaba NazariSamsoon InayatJordan C DudleyAnnie BarbeauLionel FrouxAntoine G GodinMajid H MohajeraniYves de KoninckPublished in: Brain : a journal of neurology (2023)
Disinhibition during early stages of Alzheimer's disease is postulated to cause network dysfunction and hyperexcitability leading to cognitive deficits. However, the underlying molecular mechanism remains unknown. Here we show that, in mouse lines carrying Alzheimer's disease-related mutations, a loss of neuronal membrane potassium-chloride cotransporter KCC2, responsible for maintaining the robustness of GABAA-mediated inhibition, occurs pre-symptomatically in the hippocampus and prefrontal cortex. KCC2 downregulation was inversely correlated with the age-dependent increase in amyloid-β 42 (Aβ42). Acute administration of Aβ42 caused a downregulation of membrane KCC2. Loss of KCC2 resulted in impaired chloride homeostasis. Preventing the decrease in KCC2 using long term treatment with CLP290 protected against deterioration of learning and cortical hyperactivity. In addition, restoring KCC2, using short term CLP290 treatment, following the transporter reduction effectively reversed spatial memory deficits and social dysfunction, linking chloride dysregulation with Alzheimer's disease-related cognitive decline. These results reveal KCC2 hypofunction as a viable target for treatment of Alzheimer's disease-related cognitive decline, it confirms target engagement, where the therapeutic intervention takes place, and its effectiveness.
Keyphrases
- cognitive decline
- mild cognitive impairment
- randomized controlled trial
- prefrontal cortex
- healthcare
- cell proliferation
- traumatic brain injury
- systematic review
- oxidative stress
- social media
- gene expression
- combination therapy
- brain injury
- dna methylation
- subarachnoid hemorrhage
- replacement therapy
- cognitive impairment
- liver failure
- extracorporeal membrane oxygenation
- mechanical ventilation