Louise Kelly1, Mohsen Seifi1,2, Ruolin Ma1, Scott J Mitchell3, Uwe Rudolph4, Kirsten L Viola5, William L Klein5, Jeremy J Lambert3, Jerome D Swinny1. 1. School of Pharmacy & Biomedical Sciences, University of Portsmouth, Portsmouth, UK. 2. Leicester School of Pharmacy, De Montfort University, Leicester, UK. 3. Neuroscience, Division of Systems Medicine, Ninewells Hospital & Medical School, Dundee University, Dundee, UK. 4. Department of Comparative Biosciences, College of Veterinary Medicine, and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA. 5. Department of Neurobiology and Physiology, Northwestern University, Evanston, IL, USA.
Abstract
AIMS: 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 patients. Therefore, the aim of the study 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). 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 (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. 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-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.
AIMS: 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 patients. Therefore, the aim of the study 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). 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 (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. 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-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.
Authors: Michael A Kelberman; Claire R Anderson; Eli Chlan; Jacki M Rorabaugh; Katharine E McCann; David Weinshenker Journal: J Alzheimers Dis Date: 2022 Impact factor: 4.472
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Authors: Prokopis C Prokopiou; Nina Engels-Domínguez; Kathryn V Papp; Matthew R Scott; Aaron P Schultz; Christoph Schneider; Michelle E Farrell; Rachel F Buckley; Yakeel T Quiroz; Georges El Fakhri; Dorene M Rentz; Reisa A Sperling; Keith A Johnson; Heidi I L Jacobs Journal: Nat Commun Date: 2022-03-23 Impact factor: 17.694