Knock-in models related to Alzheimer’s disease: synaptic transmission, plaques and the role of microglia

Molecular Neurodegeneration

John Hardy¹  Bart De Strooper²  Karina S. Vitanova³  Diana P. Benitez³  Natalie Wong³  Takshashila Tripathi³  Jack Wood³  Carlijn Peerboom⁴  Victoria C. Smith⁵  Dervis A. Salih⁶  Damian M. Cummings⁶  Katie M. Stringer⁷  Dhaval Joshi⁸  Rui Wang⁹  Frances A. Edwards^1,10  Shenyi Jiang^1,11  Chloe M. Hall^1,12  Jörg Hanrieder^1,13  Takaomi C. Saido^1,14  Takashi Saito^1,15 

[1] Dementia Research Institute, University College London, Gower Street, WC1E 6BT, London, UK;Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, 1 Wakefield Street, WC1N 1PJ, London, UK;UCL Movement Disorders Centre, University College London, London, UK;Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong, SAR, China;Dementia Research Institute, University College London, Gower Street, WC1E 6BT, London, UK;VIB Center for Brain & Disease Research, 3000, Leuven, KU, Belgium;Department of Neurosciences, Leuven Brain Institute, 3000, Leuven, Belgium;Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, WC1E 6BT, London, UK;Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, WC1E 6BT, London, UK;Cell Biology, Neurobiology and Biophysics, Biology Department, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands;Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, WC1E 6BT, London, UK;Centre for Doctoral Training at the Institute of Health Informatics, University College London, 222 Euston Road, NW1 2DA, London, UK;Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, WC1E 6BT, London, UK;Dementia Research Institute, University College London, Gower Street, WC1E 6BT, London, UK;Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, WC1E 6BT, London, UK;Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden;Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, WC1E 6BT, London, UK;Department of Psychology, University of Cambridge, Cambridge, UK;Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, WC1E 6BT, London, UK;Institute for Synaptic Physiology, Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, WC1E 6BT, London, UK;Institute of Healthy Ageing, University College London, Gower Street, WC1E 6BT, London, UK;Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, WC1E 6BT, London, UK;Ludwig Maximilians Universitat, Munich, Germany;Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, WC1E 6BT, London, UK;School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, UK;Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden;Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, Queen Square, WC1N 3BG, London, UK;Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, 2-1 Wako-shi, 351-0198, Saitama, Japan;Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, 2-1 Wako-shi, 351-0198, Saitama, Japan;Department of Neurocognitive Science, Institute of Brain Science, Nagoya City, University Graduate School of Medical Sciences, Nagoya, Aichi, Japan;

关键词: Synaptic transmission;    Synaptic plasticity;    Microglia;    Alzheimer’s disease;    Gene expression;    Neurodegeneration;    TREM2;    Ageing;    Amyloid beta;    Plaques;   

DOI  :  10.1186/s13024-021-00457-0

来源: Springer

【 摘 要 】

BackgroundMicroglia are active modulators of Alzheimer’s disease but their role in relation to amyloid plaques and synaptic changes due to rising amyloid beta is unclear. We add novel findings concerning these relationships and investigate which of our previously reported results from transgenic mice can be validated in knock-in mice, in which overexpression and other artefacts of transgenic technology are avoided.MethodsAppNL-F and AppNL-G-F knock-in mice expressing humanised amyloid beta with mutations in App that cause familial Alzheimer’s disease were compared to wild type mice throughout life. In vitro approaches were used to understand microglial alterations at the genetic and protein levels and synaptic function and plasticity in CA1 hippocampal neurones, each in relationship to both age and stage of amyloid beta pathology. The contribution of microglia to neuronal function was further investigated by ablating microglia with CSF1R inhibitor PLX5622.ResultsBoth App knock-in lines showed increased glutamate release probability prior to detection of plaques. Consistent with results in transgenic mice, this persisted throughout life in AppNL-F mice but was not evident in AppNL-G-F with sparse plaques. Unlike transgenic mice, loss of spontaneous excitatory activity only occurred at the latest stages, while no change could be detected in spontaneous inhibitory synaptic transmission or magnitude of long-term potentiation. Also, in contrast to transgenic mice, the microglial response in both App knock-in lines was delayed until a moderate plaque load developed. Surviving PLX5266-depleted microglia tended to be CD68-positive. Partial microglial ablation led to aged but not young wild type animals mimicking the increased glutamate release probability in App knock-ins and exacerbated the App knock-in phenotype. Complete ablation was less effective in altering synaptic function, while neither treatment altered plaque load.ConclusionsIncreased glutamate release probability is similar across knock-in and transgenic mouse models of Alzheimer’s disease, likely reflecting acute physiological effects of soluble amyloid beta. Microglia respond later to increased amyloid beta levels by proliferating and upregulating Cd68 and Trem2. Partial depletion of microglia suggests that, in wild type mice, alteration of surviving phagocytic microglia, rather than microglial loss, drives age-dependent effects on glutamate release that become exacerbated in Alzheimer’s disease.

【 授权许可】

CC BY