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

Huan Du,Junke Zhang,Man Ying Wong,Wenjie Luo,Charlene Hsu,Haiyuan Yu,Tingting Zhang,Fenghua Hu,Mariela Nunez Santos

doi:10.26508/lsa.202000874

Huan Du, Junke Zhang + Show 7 more

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https://doi.org/10.26508/lsa.202000874

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Abstract

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.

Highlights

Progranulin (PGRN), encoded by the granulin (GRN) gene in humans, has been shown to be a key player in brain aging and neurodegenerative diseases
PGRN has been implicated in Alzheimer’s disease (AD), the exact role of PGRN in AD disease progression remains unclear
We examined the role of PGRN in Aβ dynamics using the 5XFAD mice which express human amyloid precursor protein (APP) and presenilin1 transgenes containing five AD-linked mutations

Summary

Introduction

Progranulin (PGRN), encoded by the granulin (GRN) gene in humans, has been shown to be a key player in brain aging and neurodegenerative diseases. PGRN haploinsufficiency resulting from mutations in the GRN gene, is one of the major causes of frontotemporal lobar degeneration (FTLD) with TDP-43 positive inclusions (Baker et al, 2006; Cruts et al, 2006; Gass et al, 2006). Complete loss of PGRN in humans is known to cause neuronal ceroid lipofuscinosis (NCL) (Smith et al, 2012; Almeida et al, 2016), a group of lysosomal storage diseases. GRN is one of the five risk factors for a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE) (Nelson et al, 2019). PGRN polymorphisms contribute to the risk of Alzheimer’s disease (AD) (Kamalainen et al, 2013; Perry et al, 2013; Sheng et al, 2014; Xu et al, 2017), and serum PGRN levels are inversely proportional to the risk of AD development (Hsiung et al, 2011)

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