Identification of intraneuronal amyloid beta oligomers in locus coeruleus neurons of Alzheimer’s patients and their potential impact on inhibitory neurotransmitter receptors and neuronal excitability
Research output: Contribution to journal › Article › peer-review
Methods and Results: Immunohistochemistry and confocal microscopy, using AβO‐specific antibodies, confirmed LC AβO expression both intraneuronally and extracellularly in both Alzheimer’s and APP‐PSEN1 samples. Patch clamp electrophysiology recordings revealed that 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 (GABAAR) α3 subunit. This altered LC α3‐GABAAR expression profile overlapped with AβO expression in samples from both APP‐PSEN1 mice and Alzheimer’s patients. Finally, strychnine‐sensitive glycine receptors (GlyRs) remained resilient to Aβ‐induced changes and their activation reversed LC hyperexcitability.
Conclusions: The data suggest a close association between AβO and α3‐GABAARs 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.
|Journal||Neuropathology and Applied Neurobiology|
|Early online date||20 Dec 2020|
|Publication status||Early online - 20 Dec 2020|
Rights statement: This is the peer reviewed version of the following article: Kelly, L., Seifi, M., Ma, R., Mitchell, S.J., Rudolph, U., Viola, K.L., Klein, W.L., Lambert, J.J. and Swinny, J.D. (2021), Identification of intraneuronal amyloid beta oligomers in locus coeruleus neurons of Alzheimer’s patients and their potential impact on inhibitory neurotransmitter receptors and neuronal excitability. Neuropathol Appl Neurobiol. Ahead of print, which has been published in final form at https://doi.org/10.1111/nan.12674. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
Accepted author manuscript (Post-print), 63.8 MB, PDF document
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