Microglial Expression of the Wnt Signaling Modulator DKK2 Differs between Human Alzheimer's Disease Brains and Mouse Neurodegeneration Models.

Autor:	Aghaizu ND; United Kingdom Dementia Research Institute at University College London, London WC1E 6BT, United Kingdom nozie.aghaizu@ucl.ac.uk sarah.jolly@ucl.ac.uk., Jolly S; Alzheimer's Research UK Drug Discovery Institute (DDI), University College London, London WC1E 6BT, United Kingdom nozie.aghaizu@ucl.ac.uk sarah.jolly@ucl.ac.uk., Samra SK; United Kingdom Dementia Research Institute at University College London, London WC1E 6BT, United Kingdom., Kalmar B; Department of Neuromuscular Diseases, University College London Queen Square Motor Neuron Disease Centre, Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom., Craessaerts K; Vlaams Instituut voor Biotechnologie Centre for Brain Disease Research, Leuven 3000, Belgium.; Department of Neurosciences and Leuven Brain Institute, Katholieke Universiteit Leuven, Leuven 3000, Belgium., Greensmith L; Department of Neuromuscular Diseases, University College London Queen Square Motor Neuron Disease Centre, Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom., Salinas PC; Department of Cell and Developmental Biology, University College London, London WC1E 6BT, United Kingdom., De Strooper B; United Kingdom Dementia Research Institute at University College London, London WC1E 6BT, United Kingdom.; Vlaams Instituut voor Biotechnologie Centre for Brain Disease Research, Leuven 3000, Belgium.; Department of Neurosciences and Leuven Brain Institute, Katholieke Universiteit Leuven, Leuven 3000, Belgium., Whiting PJ; United Kingdom Dementia Research Institute at University College London, London WC1E 6BT, United Kingdom.; Alzheimer's Research UK Drug Discovery Institute (DDI), University College London, London WC1E 6BT, United Kingdom.
Jazyk:	angličtina
Zdroj:	ENeuro [eNeuro] 2023 Jan 11; Vol. 10 (1). Date of Electronic Publication: 2023 Jan 11 (Print Publication: 2023).
DOI:	10.1523/ENEURO.0306-22.2022
Abstrakt:	Wnt signaling is crucial for synapse and cognitive function. Indeed, deficient Wnt signaling is causally related to increased expression of DKK1, an endogenous negative Wnt regulator, and synapse loss, both of which likely contribute to cognitive decline in Alzheimer's disease (AD). Increasingly, AD research efforts have probed the neuroinflammatory role of microglia, the resident immune cells of the CNS, which have furthermore been shown to be modulated by Wnt signaling. The DKK1 homolog DKK2 has been previously identified as an activated response and/or disease-associated microglia (DAM/ARM) gene in a mouse model of AD. Here, we performed a detailed analysis of DKK2 in mouse models of neurodegeneration, and in human AD brain. In APP/PS1 and APP NL-G-F AD mouse model brains as well as in SOD1 G93A ALS mouse model spinal cords, but not in control littermates, we demonstrated significant microgliosis and microglial Dkk2 mRNA upregulation in a disease-stage-dependent manner. In the AD models, these DAM/ARM Dkk2 + microglia preferentially accumulated close to βAmyloid plaques. Furthermore, recombinant DKK2 treatment of rat hippocampal primary neurons blocked WNT7a-induced dendritic spine and synapse formation, indicative of an anti-synaptic effect similar to that of DKK1. In stark contrast, no such microglial DKK2 upregulation was detected in the postmortem human frontal cortex from individuals diagnosed with AD or pathologic aging. In summary, the difference in microglial expression of the DAM/ARM gene DKK2 between mouse models and human AD brain highlights the increasingly recognized limitations of using mouse models to recapitulate facets of human neurodegenerative disease. Competing Interests: The authors declare no competing financial interests. (Copyright © 2023 Aghaizu et al.)
Databáze:	MEDLINE
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