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
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...
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| Veröffentlicht in: | Neuropathology and applied neurobiology 2021-06, Vol.47 (4), p.488-505 |
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| creator | Kelly, Louise Seifi, Mohsen Ma, Ruolin Mitchell, Scott J. Rudolph, Uwe Viola, Kirsten L. Klein, William L. Lambert, Jeremy J. Swinny, Jerome D. |
| description | 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 (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.
Amyloid β‐oligomers (AβO) mediate synaptic pathology in Alzheimer's, yet we do not know whether they are expressed in the earliest brain region to exhibit Alzheimer's pathology, the locus coeruleus (LC). Kelly et al. reveal AβO in the LC of Alzheimer's patients and that they induce neuronal hyperactivity due to impaired GABAA receptors, which is reversible by glycine receptor‐modulating drugs. |
| doi_str_mv | 10.1111/nan.12674 |
| format | Article |
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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 (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.
Amyloid β‐oligomers (AβO) mediate synaptic pathology in Alzheimer's, yet we do not know whether they are expressed in the earliest brain region to exhibit Alzheimer's pathology, the locus coeruleus (LC). Kelly et al. reveal AβO in the LC of Alzheimer's patients and that they induce neuronal hyperactivity due to impaired GABAA receptors, which is reversible by glycine receptor‐modulating drugs.</description><identifier>ISSN: 0305-1846</identifier><identifier>EISSN: 1365-2990</identifier><identifier>DOI: 10.1111/nan.12674</identifier><identifier>PMID: 33119191</identifier><language>eng</language><publisher>England: Wiley Subscription Services, Inc</publisher><subject>Alzheimer Disease - metabolism ; Alzheimer Disease - pathology ; Alzheimer's disease ; Amyloid beta-Peptides - metabolism ; Animals ; Cognition ; Confocal microscopy ; dementia ; Disease Models, Animal ; Electrophysiology ; Excitability ; GABA‐A receptors ; Glycine receptors ; glycine transporters ; Humans ; Immune response ; Immunohistochemistry ; Immunomodulation ; Locus coeruleus ; Locus Coeruleus - metabolism ; Locus Coeruleus - pathology ; Locus Coeruleus - physiopathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neurodegenerative diseases ; Neuromodulation ; Neurons - metabolism ; Neurons - pathology ; Neurons - physiology ; Neurotransmitter receptors ; noradrenaline ; Norepinephrine ; psychosocial stress ; Strychnine ; γ-Aminobutyric acid A receptors</subject><ispartof>Neuropathology and applied neurobiology, 2021-06, Vol.47 (4), p.488-505</ispartof><rights>2020 British Neuropathological Society</rights><rights>2020 British Neuropathological Society.</rights><rights>Copyright © 2021 British Neuropathological Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3884-6c334cf9da4de8192cef97590d79a9f3454cf851f7b49841f1dcf470675ae5833</citedby><cites>FETCH-LOGICAL-c3884-6c334cf9da4de8192cef97590d79a9f3454cf851f7b49841f1dcf470675ae5833</cites><orcidid>0000-0002-8194-5481</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fnan.12674$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fnan.12674$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33119191$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kelly, Louise</creatorcontrib><creatorcontrib>Seifi, Mohsen</creatorcontrib><creatorcontrib>Ma, Ruolin</creatorcontrib><creatorcontrib>Mitchell, Scott J.</creatorcontrib><creatorcontrib>Rudolph, Uwe</creatorcontrib><creatorcontrib>Viola, Kirsten L.</creatorcontrib><creatorcontrib>Klein, William L.</creatorcontrib><creatorcontrib>Lambert, Jeremy J.</creatorcontrib><creatorcontrib>Swinny, Jerome D.</creatorcontrib><title>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</title><title>Neuropathology and applied neurobiology</title><addtitle>Neuropathol Appl Neurobiol</addtitle><description>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 (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.
Amyloid β‐oligomers (AβO) mediate synaptic pathology in Alzheimer's, yet we do not know whether they are expressed in the earliest brain region to exhibit Alzheimer's pathology, the locus coeruleus (LC). Kelly et al. reveal AβO in the LC of Alzheimer's patients and that they induce neuronal hyperactivity due to impaired GABAA receptors, which is reversible by glycine receptor‐modulating drugs.</description><subject>Alzheimer Disease - metabolism</subject><subject>Alzheimer Disease - pathology</subject><subject>Alzheimer's disease</subject><subject>Amyloid beta-Peptides - metabolism</subject><subject>Animals</subject><subject>Cognition</subject><subject>Confocal microscopy</subject><subject>dementia</subject><subject>Disease Models, Animal</subject><subject>Electrophysiology</subject><subject>Excitability</subject><subject>GABA‐A receptors</subject><subject>Glycine receptors</subject><subject>glycine transporters</subject><subject>Humans</subject><subject>Immune response</subject><subject>Immunohistochemistry</subject><subject>Immunomodulation</subject><subject>Locus coeruleus</subject><subject>Locus Coeruleus - metabolism</subject><subject>Locus Coeruleus - pathology</subject><subject>Locus Coeruleus - physiopathology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Transgenic</subject><subject>Neurodegenerative diseases</subject><subject>Neuromodulation</subject><subject>Neurons - metabolism</subject><subject>Neurons - pathology</subject><subject>Neurons - physiology</subject><subject>Neurotransmitter receptors</subject><subject>noradrenaline</subject><subject>Norepinephrine</subject><subject>psychosocial stress</subject><subject>Strychnine</subject><subject>γ-Aminobutyric acid A receptors</subject><issn>0305-1846</issn><issn>1365-2990</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kU9u1TAQhy0Eoo_CggsgS2xgkdaO7SRePlX8qVSVDawjx5lQV04cbEclrHqNHolrcBLmkdIFEvbClubzNyP_CHnJ2QnHdTqZ6YSXVS0fkR0XlSpKrdljsmOCqYI3sjoiz1K6ZoyputJPyZEQnGvcO_LzvIcpu8FZk12YaBiom3I0EywxTMZTM64-uJ52kA0N3n0NI8SEEPXBLonaAHHxgLftSToo9v7HFTgEf93eJTqjGpskaqaeZixEOod8aIt-N87GZoqt3XTlOpdDXDfVYYo0upwh0ggWZixtjofh4Lt12XTOu7w-J08G4xO8uD-PyZf37z6ffSwuPn04P9tfFFY0jSwqK4S0g-6N7KHhurQw6Fpp1tfa6EFIhdVG8aHupG4kH3hvB1mzqlYGVCPEMXmzeecYvi2Qcju6ZMF7_LOwpLaUSjUSP_iAvv4HvQ5LxMGRUiWrGgyLI_V2o2wMKUUY2jm60cS15aw95Ntivu2ffJF9dW9cuhH6B_JvoAicbsCN87D-39Re7i835W-XnrZ8</recordid><startdate>202106</startdate><enddate>202106</enddate><creator>Kelly, Louise</creator><creator>Seifi, Mohsen</creator><creator>Ma, Ruolin</creator><creator>Mitchell, Scott J.</creator><creator>Rudolph, Uwe</creator><creator>Viola, Kirsten L.</creator><creator>Klein, William L.</creator><creator>Lambert, Jeremy J.</creator><creator>Swinny, Jerome D.</creator><general>Wiley Subscription Services, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>K9.</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-8194-5481</orcidid></search><sort><creationdate>202106</creationdate><title>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</title><author>Kelly, Louise ; Seifi, Mohsen ; Ma, Ruolin ; Mitchell, Scott J. ; Rudolph, Uwe ; Viola, Kirsten L. ; Klein, William L. ; Lambert, Jeremy J. ; Swinny, Jerome D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3884-6c334cf9da4de8192cef97590d79a9f3454cf851f7b49841f1dcf470675ae5833</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Alzheimer Disease - metabolism</topic><topic>Alzheimer Disease - pathology</topic><topic>Alzheimer's disease</topic><topic>Amyloid beta-Peptides - metabolism</topic><topic>Animals</topic><topic>Cognition</topic><topic>Confocal microscopy</topic><topic>dementia</topic><topic>Disease Models, Animal</topic><topic>Electrophysiology</topic><topic>Excitability</topic><topic>GABA‐A receptors</topic><topic>Glycine receptors</topic><topic>glycine transporters</topic><topic>Humans</topic><topic>Immune response</topic><topic>Immunohistochemistry</topic><topic>Immunomodulation</topic><topic>Locus coeruleus</topic><topic>Locus Coeruleus - metabolism</topic><topic>Locus Coeruleus - pathology</topic><topic>Locus Coeruleus - physiopathology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Transgenic</topic><topic>Neurodegenerative diseases</topic><topic>Neuromodulation</topic><topic>Neurons - metabolism</topic><topic>Neurons - pathology</topic><topic>Neurons - physiology</topic><topic>Neurotransmitter receptors</topic><topic>noradrenaline</topic><topic>Norepinephrine</topic><topic>psychosocial stress</topic><topic>Strychnine</topic><topic>γ-Aminobutyric acid A receptors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kelly, Louise</creatorcontrib><creatorcontrib>Seifi, Mohsen</creatorcontrib><creatorcontrib>Ma, Ruolin</creatorcontrib><creatorcontrib>Mitchell, Scott J.</creatorcontrib><creatorcontrib>Rudolph, Uwe</creatorcontrib><creatorcontrib>Viola, Kirsten L.</creatorcontrib><creatorcontrib>Klein, William L.</creatorcontrib><creatorcontrib>Lambert, Jeremy J.</creatorcontrib><creatorcontrib>Swinny, Jerome D.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Neuropathology and applied neurobiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kelly, Louise</au><au>Seifi, Mohsen</au><au>Ma, Ruolin</au><au>Mitchell, Scott J.</au><au>Rudolph, Uwe</au><au>Viola, Kirsten L.</au><au>Klein, William L.</au><au>Lambert, Jeremy J.</au><au>Swinny, Jerome D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>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</atitle><jtitle>Neuropathology and applied neurobiology</jtitle><addtitle>Neuropathol Appl Neurobiol</addtitle><date>2021-06</date><risdate>2021</risdate><volume>47</volume><issue>4</issue><spage>488</spage><epage>505</epage><pages>488-505</pages><issn>0305-1846</issn><eissn>1365-2990</eissn><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 (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.
Amyloid β‐oligomers (AβO) mediate synaptic pathology in Alzheimer's, yet we do not know whether they are expressed in the earliest brain region to exhibit Alzheimer's pathology, the locus coeruleus (LC). Kelly et al. reveal AβO in the LC of Alzheimer's patients and that they induce neuronal hyperactivity due to impaired GABAA receptors, which is reversible by glycine receptor‐modulating drugs.</abstract><cop>England</cop><pub>Wiley Subscription Services, Inc</pub><pmid>33119191</pmid><doi>10.1111/nan.12674</doi><tpages>18</tpages><orcidid>https://orcid.org/0000-0002-8194-5481</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Neuropathology and applied neurobiology, 2021-06, Vol.47 (4), p.488-505 |
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| subjects | Alzheimer Disease - metabolism Alzheimer Disease - pathology Alzheimer's disease Amyloid beta-Peptides - metabolism Animals Cognition Confocal microscopy dementia Disease Models, Animal Electrophysiology Excitability GABA‐A receptors Glycine receptors glycine transporters Humans Immune response Immunohistochemistry Immunomodulation Locus coeruleus Locus Coeruleus - metabolism Locus Coeruleus - pathology Locus Coeruleus - physiopathology Male Mice Mice, Inbred C57BL Mice, Transgenic Neurodegenerative diseases Neuromodulation Neurons - metabolism Neurons - pathology Neurons - physiology Neurotransmitter receptors noradrenaline Norepinephrine psychosocial stress Strychnine γ-Aminobutyric acid A receptors |
| title | 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 |
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