Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.14.096396v1?rss=1 Authors: Kelly, L., Seifi, M., Ma, R., Mitchell, S., Rudolph, U., Viola, K., Klein, W. L., Lambert, J. J., Swinny, J. D. Abstract: Amyloid beta oligomers (ABO) are potent modulators of two key Alzheimer's pathological processes, namely synaptic dysfunction and tau tangle formation in various brain regions. Remarkably, the impact of ABO in one of the earliest brain regions to exhibit Alzheimer's pathology, the locus coeruleus (LC), remains to be determined. Of particular importance is the effect of ABO on the excitability of individual 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 severely compromised in Alzheimer's. Using a mouse model of increased AB production (APP-PSEN1), together with correlative histopathological analyses in post mortem Alzheimer's patient samples, we determined the impact of AB pathology on various correlates of LC neuronal integrity. ABO immunoreactivity in the LC of APP-PSEN1 mice was replicated in patient samples, presenting as individual clusters located both intraneuronally, in mitochondrial compartments, as well as extracellularly in association with inhibitory synapses. No specific signal was detected in either patient control or wild type mouse samples. Accompanying this ABO expression profile was LC neuronal hyperexcitability and indicators of oxidative stress in APP-PSEN1 mice. LC hyperexcitability arose from a diminished inhibitory effect of GABA, due to impaired expression and function of the GABA-A receptor (GABAAR) alpha 3 subunit. Importantly, this altered LC alpha 3-GABAAR expression profile overlapped with ABO expression in both APP-PSEN1 mice and Alzheimer's patient samples. Finally, strychnine-sensitive glycine receptors (GlyRs) remained resilient to ABO-induced changes and their activation reversed LC hyperexcitability. Alongside this first demonstration of ABO expression in the LC of Alzheimer's patients, the study is also first to reveal a direct association between ABO and LC neuronal excitability. GlyR-alpha3-GABAAR modulation of ABO-dependent LC hyperexcitability could delay the onset of cognitive and psychiatric symptoms arising from LC-NA deficits, thereby significantly diminishing the disease burden for Alzheimer's patients. Copy rights belong to original authors. Visit the link for more info