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

TitleA multifaceted role of progranulin in regulating amyloid-beta dynamics and responses.
Publication TypeJournal Article
Year of Publication2021
AuthorsDu H, Wong MYing, Zhang T, Santos MNunez, Hsu C, Zhang J, Yu H, Luo W, Hu F
JournalLife Sci Alliance
Date Published2021 07
KeywordsAge Factors, Alzheimer Disease, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Brain, Disease Models, Animal, Female, Frontotemporal Lobar Degeneration, Intercellular Signaling Peptides and Proteins, Lysosomes, Male, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Microglia, Plaque, Amyloid, Progranulins, Proteins, Receptors, Immunologic, Sex Factors

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.

Alternate JournalLife Sci Alliance
PubMed ID34103390
PubMed Central IDPMC8200295
Grant ListR01 NS088448 / NS / NINDS NIH HHS / United States
R01 NS095954 / NS / NINDS NIH HHS / United States
R01 AG064239 / AG / NIA NIH HHS / United States