Interaction of amyloid beta oligomers and α3-GABAA Rs in locus coeruleus neuronal excitability and Alzheimer's pathology.

Abstract

Amyloid β oligomers (AβO) are potent modulators of Alzheimer's pathology, yet their impact on one of the earliest brain regions to exhibit signs of the condition, the locus coeruleus (LC), remains to be determined. Of particular importance is whether AβO impact the spontaneous excitability of LC neurons. This parameter determines brain-wide noradrenaline (NA) release, and thus NA-mediated brain functions, including cognition, emotion and immune function, which are all compromised in Alzheimer's. Therefore, the aim of this research was to determine the expression profile of AβO in the LC of Alzheimer's patients and to probe their potential impact on the molecular and functional correlates of LC excitability, using a mouse model of increased Aβ production (APP-PSEN1). Immunohistochemistry and confocal microscopy were used for correlative AβO expression analyses in samples from Alzheimer's patients and APP-PSEN1. Patch clamp electrophysiology was used to assess the impact of AβO on LC neuronal excitability and neurotransmitter receptor function. LC AβO immunoreactivity was located intraneuronally and extracellularly in both Alzheimer's and APP-PSEN1 samples. APP-PSEN1 LC neuronal hyperexcitability accompanied this AβO expression profile, arising from a diminished inhibitory effect of GABA, due to impaired expression and function of the GABA-A receptor (GABAA R) α3 subunit. This altered LC α3-GABAA R expression profile overlapped with AβO expression in samples from both APP-PSEN1 mice and Alzheimer's patients. Aged α3-GABAA R knockout mice in turn exhibited increased LC AβO expression, impaired recognition memory, neuroinflammation and decreased brain volume, suggesting a direct interaction between α3-GABAA R, AβO pathways and Alzheimer's-associated brain pathology. Finally, strychnine-sensitive glycine receptors remained resilient to Aβ-induced changes and their activation reversed LC hyperexcitability. The data suggest a close association between AβO and α3-GABAA Rs in the LC of Alzheimer's patients, and their potential to dysregulate LC activity, thereby contributing to the spectrum of pathology of the LC-NA system in this condition.