The yin and yang of TDP-43 reduction

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Science  28 Jul 2017:
Vol. 357, Issue 6349, pp. 367
DOI: 10.1126/science.357.6349.367-a

TDP-43 in microglia reduces brain amyloid, but with a cost.


The gene that encodes TDP-43 is implicated in fronto-temporal lobar degeneration and amyotrophic lateral sclerosis. Microglia are the brain's innate immune cells, constantly surveying for anything that might interfere with correct brain functions. Paolicelli et al. suggest that TDP-43 is a regulator of microglia function. In an inducible conditional knockout mouse line crossed to an Alzheimer's mouse model, the depletion of TDP-43 from brain microglia resulted in a decrease in brain amyloid. Such a reduction in amyloid might be construed as beneficial. However, the mice also exhibited a reduction in synaptic markers and displayed signs of neurodegeneration. Thus, TDP-43 plays a role in modulating microglia-mediated clearance. In neurodegeneration, such abnormal phagocytic activity could be detrimental if it promotes excessive microglial-mediated synaptic removal, despite enhanced amyloid clearance.

Neuron 10.1016/j.neuron.2017.05.037 (2017).

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