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bioRxiv · 10.1101/2021.04.12.439509

A multifaceted role of progranulin in regulating amyloid-beta dynamics and responses

Du, H.·Wong, M. Y.·Zhang, T.·Nunez Santos, M.·Hsu, C.·Zhang, J.·Yu, H.·Luo, W.·Hu, F.
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Abstract

Haploinsufficiency of progranulin (PGRN) is a leading cause of frontotemporal lobar degeneration (FTLD). PGRN polymorphisms are associated with Alzheimers disease (AD). PGRN is highly expressed in the microglia near A{beta} plaques and influences plaque dynamics and microglial activation. However, the detailed mechanisms remain elusive. Here we report that PGRN deficiency reduces human APP and A{beta} levels in the young male but not female mice. PGRN deficient microglia exhibit increased expression of markers associated with microglial activation, including CD68, Galectin-3, TREM2 and GPNMB, specifically near A{beta} plaques. In addition, PGRN loss leads to up-regulation of lysosome proteins and an increase in the nuclear localization of TFE3, a transcription factor involved in lysosome biogenesis. Cultured PGRN deficient microglia show enhanced nuclear translocation of TFE3 and inflammation in response to A{beta} fibril treatment. Taken together, our data revealed a sex- and age-dependent effect of PGRN on amyloid metabolism and a role of PGRN in regulating lysosomal activities and inflammation in plaque-associated microglia, which may contribute to the disease mechanism associated with PGRN polymorphisms in AD.

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Du, H., Wong, M. Y., Zhang, T., Nunez Santos, M., Hsu, C., Zhang, J., Yu, H., Luo, W., Hu, F.. 2021-04-14. A multifaceted role of progranulin in regulating amyloid-beta dynamics and responses. https://doi.org/10.1101/2021.04.12.439509

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