Microglia play a part in protein clearance and synaptic pruning. This latter process is re-activated in Alzheimer disease (AD) and promoted by amyloid-β (Aβ). A screen of 18 AD-associated genes revealed that loss of the DNA–RNA binding protein TDP43 led to a considerable increase in phagocytic clearance of Aβ by microglia. Selective knockout of TDP43 from microglia in a mouse model of AD resulted in increased Aβ clearance but, unexpectedly, increased synapse loss. Consistent with this, people with TDP43 pathology had lower Aβ load and a lower risk of AD but showed a small cognitive deficit. Therefore, microglial dysfunction could contribute to AD pathology.
References
Paolicelli, R. C. et al. TDP-43 depletion in microglia promotes amyloid clearance but also induces synapse loss. Neuron http://dx.doi.org/10.1016/j.neuron.2017.05.037 (2017)
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Lewis, S. Amyloid clearance. Nat Rev Neurosci 18, 455 (2017). https://doi.org/10.1038/nrn.2017.97
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DOI: https://doi.org/10.1038/nrn.2017.97
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