Effects of rising amyloidβ levels on hippocampal synaptic transmission, microglial response and cognition in APPSwe/PSEN1M146V transgenic miceResearch in context
Background: Progression of Alzheimer's disease is thought initially to depend on rising amyloidβ and its synaptic interactions. Transgenic mice (TASTPM; APPSwe/PSEN1M146V) show altered synaptic transmission, compatible with increased physiological function of amyloidβ, before plaques are detect...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-01-01
|
| Series: | EBioMedicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396418305772 |
| _version_ | 1828816303184412672 |
|---|---|
| author | Evelyn Medawar Tiffanie A. Benway Wenfei Liu Taylor A. Hanan Peter Haslehurst Owain T. James Kenrick Yap Laurenz Muessig Fabia Moroni Muzammil A. Nahaboo Solim Gaukhar Baidildinova Rui Wang Jill C. Richardson Francesca Cacucci Dervis A. Salih Damian M. Cummings Frances A. Edwards |
| author_facet | Evelyn Medawar Tiffanie A. Benway Wenfei Liu Taylor A. Hanan Peter Haslehurst Owain T. James Kenrick Yap Laurenz Muessig Fabia Moroni Muzammil A. Nahaboo Solim Gaukhar Baidildinova Rui Wang Jill C. Richardson Francesca Cacucci Dervis A. Salih Damian M. Cummings Frances A. Edwards |
| author_sort | Evelyn Medawar |
| collection | DOAJ |
| description | Background: Progression of Alzheimer's disease is thought initially to depend on rising amyloidβ and its synaptic interactions. Transgenic mice (TASTPM; APPSwe/PSEN1M146V) show altered synaptic transmission, compatible with increased physiological function of amyloidβ, before plaques are detected. Recently, the importance of microglia has become apparent in the human disease. Similarly, TASTPM show a close association of plaque load with upregulated microglial genes. Methods: CA1 synaptic transmission and plasticity were investigated using in vitro electrophysiology. Microglial relationship to plaques was examined with immunohistochemistry. Behaviour was assessed with a forced-alternation T-maze, open field, light/dark box and elevated plus maze. Findings: The most striking finding is the increase in microglial numbers in TASTPM, which, like synaptic changes, begins before plaques are detected. Further increases and a reactive phenotype occur later, concurrent with development of larger plaques. Long-term potentiation is initially enhanced at pre-plaque stages but decrements with the initial appearance of plaques. Finally, despite altered plasticity, TASTPM have little cognitive deficit, even with a heavy plaque load, although they show altered non-cognitive behaviours. Interpretation: The pre-plaque synaptic changes and microglial proliferation are presumably related to low, non-toxic amyloidβ levels in the general neuropil and not directly associated with plaques. However, as plaques grow, microglia proliferate further, clustering around plaques and becoming phagocytic. Like in humans, even when plaque load is heavy, without development of neurofibrillary tangles and neurodegeneration, these alterations do not result in cognitive deficits. Behaviours are seen that could be consistent with pre-diagnosis changes in the human condition. Funding: GlaxoSmithKline; BBSRC; UCL; ARUK; MRC. Keywords: Alzheimer's disease, Dementia, Mouse model, Synaptic transmission, Microglia, Plaque, Neurodegeneration |
| first_indexed | 2024-12-12T11:00:29Z |
| format | Article |
| id | doaj.art-5722d6f40c0e41faafdec353fb1fb985 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-12T11:00:29Z |
| publishDate | 2019-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-5722d6f40c0e41faafdec353fb1fb9852022-12-22T00:26:32ZengElsevierEBioMedicine2352-39642019-01-0139422435Effects of rising amyloidβ levels on hippocampal synaptic transmission, microglial response and cognition in APPSwe/PSEN1M146V transgenic miceResearch in contextEvelyn Medawar0Tiffanie A. Benway1Wenfei Liu2Taylor A. Hanan3Peter Haslehurst4Owain T. James5Kenrick Yap6Laurenz Muessig7Fabia Moroni8Muzammil A. Nahaboo Solim9Gaukhar Baidildinova10Rui Wang11Jill C. Richardson12Francesca Cacucci13Dervis A. Salih14Damian M. Cummings15Frances A. Edwards16Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.; Institute of Cellular Medicine, Newcastle University Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.; Department of Science and Innovations, Asfendiyarov Kazakh National Medical University, Zhamakayev Street, Almaty, A26P6B5, Kazakhstan.Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.; Corresponding authors.Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.; Corresponding authors.Background: Progression of Alzheimer's disease is thought initially to depend on rising amyloidβ and its synaptic interactions. Transgenic mice (TASTPM; APPSwe/PSEN1M146V) show altered synaptic transmission, compatible with increased physiological function of amyloidβ, before plaques are detected. Recently, the importance of microglia has become apparent in the human disease. Similarly, TASTPM show a close association of plaque load with upregulated microglial genes. Methods: CA1 synaptic transmission and plasticity were investigated using in vitro electrophysiology. Microglial relationship to plaques was examined with immunohistochemistry. Behaviour was assessed with a forced-alternation T-maze, open field, light/dark box and elevated plus maze. Findings: The most striking finding is the increase in microglial numbers in TASTPM, which, like synaptic changes, begins before plaques are detected. Further increases and a reactive phenotype occur later, concurrent with development of larger plaques. Long-term potentiation is initially enhanced at pre-plaque stages but decrements with the initial appearance of plaques. Finally, despite altered plasticity, TASTPM have little cognitive deficit, even with a heavy plaque load, although they show altered non-cognitive behaviours. Interpretation: The pre-plaque synaptic changes and microglial proliferation are presumably related to low, non-toxic amyloidβ levels in the general neuropil and not directly associated with plaques. However, as plaques grow, microglia proliferate further, clustering around plaques and becoming phagocytic. Like in humans, even when plaque load is heavy, without development of neurofibrillary tangles and neurodegeneration, these alterations do not result in cognitive deficits. Behaviours are seen that could be consistent with pre-diagnosis changes in the human condition. Funding: GlaxoSmithKline; BBSRC; UCL; ARUK; MRC. Keywords: Alzheimer's disease, Dementia, Mouse model, Synaptic transmission, Microglia, Plaque, Neurodegenerationhttp://www.sciencedirect.com/science/article/pii/S2352396418305772 |
| spellingShingle | Evelyn Medawar Tiffanie A. Benway Wenfei Liu Taylor A. Hanan Peter Haslehurst Owain T. James Kenrick Yap Laurenz Muessig Fabia Moroni Muzammil A. Nahaboo Solim Gaukhar Baidildinova Rui Wang Jill C. Richardson Francesca Cacucci Dervis A. Salih Damian M. Cummings Frances A. Edwards Effects of rising amyloidβ levels on hippocampal synaptic transmission, microglial response and cognition in APPSwe/PSEN1M146V transgenic miceResearch in context EBioMedicine |
| title | Effects of rising amyloidβ levels on hippocampal synaptic transmission, microglial response and cognition in APPSwe/PSEN1M146V transgenic miceResearch in context |
| title_full | Effects of rising amyloidβ levels on hippocampal synaptic transmission, microglial response and cognition in APPSwe/PSEN1M146V transgenic miceResearch in context |
| title_fullStr | Effects of rising amyloidβ levels on hippocampal synaptic transmission, microglial response and cognition in APPSwe/PSEN1M146V transgenic miceResearch in context |
| title_full_unstemmed | Effects of rising amyloidβ levels on hippocampal synaptic transmission, microglial response and cognition in APPSwe/PSEN1M146V transgenic miceResearch in context |
| title_short | Effects of rising amyloidβ levels on hippocampal synaptic transmission, microglial response and cognition in APPSwe/PSEN1M146V transgenic miceResearch in context |
| title_sort | effects of rising amyloidβ levels on hippocampal synaptic transmission microglial response and cognition in appswe psen1m146v transgenic miceresearch in context |
| url | http://www.sciencedirect.com/science/article/pii/S2352396418305772 |
| work_keys_str_mv | AT evelynmedawar effectsofrisingamyloidblevelsonhippocampalsynaptictransmissionmicroglialresponseandcognitioninappswepsen1m146vtransgenicmiceresearchincontext AT tiffanieabenway effectsofrisingamyloidblevelsonhippocampalsynaptictransmissionmicroglialresponseandcognitioninappswepsen1m146vtransgenicmiceresearchincontext AT wenfeiliu effectsofrisingamyloidblevelsonhippocampalsynaptictransmissionmicroglialresponseandcognitioninappswepsen1m146vtransgenicmiceresearchincontext AT taylorahanan effectsofrisingamyloidblevelsonhippocampalsynaptictransmissionmicroglialresponseandcognitioninappswepsen1m146vtransgenicmiceresearchincontext AT peterhaslehurst effectsofrisingamyloidblevelsonhippocampalsynaptictransmissionmicroglialresponseandcognitioninappswepsen1m146vtransgenicmiceresearchincontext AT owaintjames effectsofrisingamyloidblevelsonhippocampalsynaptictransmissionmicroglialresponseandcognitioninappswepsen1m146vtransgenicmiceresearchincontext AT kenrickyap effectsofrisingamyloidblevelsonhippocampalsynaptictransmissionmicroglialresponseandcognitioninappswepsen1m146vtransgenicmiceresearchincontext AT laurenzmuessig effectsofrisingamyloidblevelsonhippocampalsynaptictransmissionmicroglialresponseandcognitioninappswepsen1m146vtransgenicmiceresearchincontext AT fabiamoroni effectsofrisingamyloidblevelsonhippocampalsynaptictransmissionmicroglialresponseandcognitioninappswepsen1m146vtransgenicmiceresearchincontext AT muzammilanahaboosolim effectsofrisingamyloidblevelsonhippocampalsynaptictransmissionmicroglialresponseandcognitioninappswepsen1m146vtransgenicmiceresearchincontext AT gaukharbaidildinova effectsofrisingamyloidblevelsonhippocampalsynaptictransmissionmicroglialresponseandcognitioninappswepsen1m146vtransgenicmiceresearchincontext AT ruiwang effectsofrisingamyloidblevelsonhippocampalsynaptictransmissionmicroglialresponseandcognitioninappswepsen1m146vtransgenicmiceresearchincontext AT jillcrichardson effectsofrisingamyloidblevelsonhippocampalsynaptictransmissionmicroglialresponseandcognitioninappswepsen1m146vtransgenicmiceresearchincontext AT francescacacucci effectsofrisingamyloidblevelsonhippocampalsynaptictransmissionmicroglialresponseandcognitioninappswepsen1m146vtransgenicmiceresearchincontext AT dervisasalih effectsofrisingamyloidblevelsonhippocampalsynaptictransmissionmicroglialresponseandcognitioninappswepsen1m146vtransgenicmiceresearchincontext AT damianmcummings effectsofrisingamyloidblevelsonhippocampalsynaptictransmissionmicroglialresponseandcognitioninappswepsen1m146vtransgenicmiceresearchincontext AT francesaedwards effectsofrisingamyloidblevelsonhippocampalsynaptictransmissionmicroglialresponseandcognitioninappswepsen1m146vtransgenicmiceresearchincontext |