Identification of amyloid beta oligomers in locus coeruleus (LC) neurons of Alzheimer's patients and their impact on LC oxidative stress, inhibitory neurotransmitter receptors and neuronal excitability

Abstract

Amyloid {beta} oligomers (A{beta}O) are potent modulators of two key Alzheimers pathological processes, namely synaptic dysfunction and tau tangle formation in various brain regions. Remarkably, the impact of A{beta}O in one of the earliest brain regions to exhibit Alzheimers pathology, the locus coeruleus (LC), remains to be determined. Of particular importance is the effect of A{beta}O 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 Alzheimers. Using a mouse model of increased A{beta} production (APP-PSEN1), together with correlative histopathological analyses in post mortem Alzheimers patient samples, we determined the impact of A{beta} pathology on various correlates of LC neuronal integrity. A{beta}O 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 A{beta}O 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) 3 subunit. Importantly, this altered LC 3-GABAAR expression profile overlapped with A{beta}O expression in both APP-PSEN1 mice and Alzheimers patient samples. Finally, strychnine-sensitive glycine receptors (GlyRs) remained resilient to A{beta}O-induced changes and their activation reversed LC hyperexcitability. Alongside this first demonstration of A{beta}O expression in the LC of Alzheimers patients, the study is also first to reveal a direct association between A{beta}O and LC neuronal excitability. GlyR-3-GABAAR modulation of A{beta}O-dependent LC hyperexcitability could delay the onset of cognitive and psychiatric symptoms arising from LC-NA deficits, thereby significantly diminishing the disease burden for Alzheimers patients.