Restoring neuronal chloride extrusion reverses cognitive decline linked to Alzheimer’s disease mutations

Abstract

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.

Chronic optogenetic activation of hippocampal pyramidal neurons replicates the proteome footprint of Alzheimer’s disease-like pathology

“…We found that chronic optogenetic stimulation in the hippocampus of WT+SSFO mice resulted in spatial memory deficits, similar to the impairment seen here in 6-months-old 5xFAD mice (Fig. 6F), or previously described in [40].…”

“…Levels of Αβ40 and Aβ42 in hippocampal samples were quantitated by Human/Rat β Amyloid (40) ELISA kit (Wako 294-62501, LOT# WTL5240) and Human/Rat β Amyloid (42) ELISA kit (Wako 290-62601, LOT# WTM4353) respectively. Both ELISAs were performed according to the manufacturer recommendations, and the plates were read at 450 nm using a Eon microplate reader (BioTek).…”

Regulation of Neuronal Chloride Homeostasis by Pro- and Mature Brain-Derived Neurotrophic Factor (BDNF) via KCC2 Cation-Chloride Cotransporters in Rat Cortical Neurons

“…The role of KCC2 and NKCC1 in maintaining chloride homeostasis extends beyond brain development, as dysfunctions of these co-transporters are also observed in various neurodegenerative disorders, including Alzheimer's disease (AD), amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease [10]. Notably, in Alzheimer's disease, alterations in KCC2 activity occur during the presymptomatic phase and are linked to cognitive deficits [11]. Overall, while the specific mechanisms linking KCC2 to neurodegenerative diseases are still being elucidated, dysregulation of KCC2-mediated chloride homeostasis appears to be a common feature in various neurodegenerative conditions.…”

“…Changes in the expression or functionality of NKCC1 and KCC2 are associated with a range of neurological disorders. These conditions include neurodevelopmental disorders (NDD) like epilepsy, Autism Spectrum Disorders (ASD), schizophrenia, Down syndrome, and Rett syndrome [9,10], and more recently, to neurodegenerative diseases [11,12]. All these conditions have been linked to disruptions in the expression or function of these cotransporters.…”

Regulation of Neuronal Chloride Homeostasis by Pro- and Mature Brain-Derived Neurotrophic Factor (BDNF) via KCC2 Cation–Chloride Cotransporters in Rat Cortical Neurons

“…Changes in the expression or functionality of NKCC1 and KCC2 are associated with a range of neurological disorders. These conditions include neurodevelopmental disorders (NDDs) like epilepsy, autism spectrum disorder (ASD), schizophrenia, Down syndrome, and Rett syndrome [ 9 , 10 ] and, more recently, neurodegenerative diseases [ 11 , 12 ]. All these conditions have been linked to disruptions in the expression or function of these cotransporters.…”