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Published on: October 6, 2017
Microglial Expression of the Wnt Signaling Modulator DKK2 Differs between Human Alzheimer's Disease Brains and Mouse
Nozie D Aghaizu1, Sarah Jolly2, Satinder K Samra3
1United Kingdom Dementia Research Institute at University College London, London WC1E 6BT, United Kingdom nozie.aghaizu@ucl.ac.uk sarah.jolly@ucl.ac.uk.
Abstract:
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 AD mouse model brains as well as in SOD1 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.
Insights
Microglial DKK2 is upregulated in mouse models of neurodegeneration but not in human Alzheimer
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Wnt signaling is vital for cognitive function and synapse integrity.
- Deficient Wnt signaling, linked to increased DKK1 and synapse loss, contributes to Alzheimer's disease (AD) cognitive decline.
- Microglia, the CNS immune cells, are modulated by Wnt signaling and implicated in AD neuroinflammation.
Purpose of the Study:
- To investigate the role and expression of DKK2, a Wnt signaling regulator, in microglial responses during neurodegeneration.
- To compare DKK2 expression in mouse models of neurodegeneration with human AD brain tissue.
- To assess the impact of DKK2 on neuronal synapse formation.
Main Methods:
- Analysis of DKK2 mRNA levels in microglia from APP/PS1 and APP mouse models of AD, and SOD1 ALS mouse models.
- Immunohistochemical analysis to identify microglial activation and proximity to amyloid plaques.
- In vitro experiments treating primary neurons with recombinant DKK2 to assess effects on WNT7a-induced synapse formation.
Main Results:
- Significant microgliosis and microglial DKK2 mRNA upregulation were observed in AD and ALS mouse models in a disease-stage-dependent manner.
- In AD models, DKK2-expressing microglia (DAM/ARM) were found near amyloid plaques.
- Recombinant DKK2 inhibited WNT7a-induced dendritic spine and synapse formation in primary neurons, similar to DKK1.
Conclusions:
- Microglial DKK2 upregulation occurs in mouse models of neurodegeneration, suggesting a role in disease-associated microglial activation.
- DKK2 exhibits anti-synaptic effects, potentially contributing to cognitive decline.
- Crucially, microglial DKK2 upregulation was not detected in human AD brains, highlighting limitations of mouse models for human neurodegenerative diseases.
