PT  - JOURNAL ARTICLE
AU  - Huan Du
AU  - Man Ying Wong
AU  - Tingting Zhang
AU  - Mariela Nunez Santos
AU  - Charlene Hsu
AU  - Junke Zhang
AU  - Haiyuan Yu
AU  - Wenjie Luo
AU  - Fenghua Hu
TI  - A multifaceted role of progranulin in regulating amyloid-beta dynamics and responses
AID  - 10.26508/lsa.202000874
DP  - 2021 Jul 01
TA  - Life Science Alliance
PG  - e202000874
VI  - 4
IP  - 7
4099  - https://www.life-science-alliance.org/content/4/7/e202000874.short
4100  - https://www.life-science-alliance.org/content/4/7/e202000874.full
SO  - Life Sci. Alliance2021 Jul 01; 4
AB  - Haploinsufficiency of progranulin (PGRN) is a leading cause of frontotemporal lobar degeneration (FTLD). PGRN polymorphisms are associated with Alzheimer’s disease. PGRN is highly expressed in the microglia near Aβ plaques and influences plaque dynamics and microglial activation. However, the detailed mechanisms remain elusive. Here we report that PGRN deficiency reduces human APP and Aβ 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 Aβ 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 Aβ fibril treatment. Taken together, our data revealed a sex- and age-dependent effect of PGRN on APP metabolism and a role of PGRN in regulating lysosomal activities and inflammation in plaque-associated microglia.