Abstract
Progranulin (PGRN) is predominantly expressed by microglia in the brain, and genetic and experimental evidence suggests a critical role in Alzheimer's disease (AD). We asked whether PGRN expression is changed in a disease severity‐specific manner in AD. We measured PGRN in cerebrospinal fluid (CSF) in two of the best‐characterized AD patient cohorts, namely the Dominant Inherited Alzheimer's Disease Network (DIAN) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). In carriers of AD causing dominant mutations, cross‐sectionally assessed CSF PGRN increased over the course of the disease and significantly differed from non‐carriers 10 years before the expected symptom onset. In late‐onset AD, higher CSF PGRN was associated with more advanced disease stages and cognitive impairment. Higher CSF PGRN was associated with higher CSF soluble TREM2 (triggering receptor expressed on myeloid cells 2) only when there was underlying pathology, but not in controls. In conclusion, we demonstrate that, although CSF PGRN is not a diagnostic biomarker for AD, it may together with sTREM2 reflect microglial activation during the disease.
Highlights
Haploinsufficiency of the gene encoding progranulin (PGRN) leads to frontotemporal lobar degeneration (FTLD) with TAR DNA binding protein 43 (TDP-43) deposition (FTLD-TDP) (Baker et al, 2006; Cruts et al, 2006; Neumann et al, 2006)
We conducted an analysis of covariance (ANCOVA) controlling for age, gender and APOE e4 status, and we found that cerebrospinal fluid (CSF) PGRN significantly differed between groups (F4,594 = 7.32, P < 0.0001)
In a linear regression model, we found that CSF PGRN and CSF sTREM2 were significantly associated in autosomal dominant AD (ADAD) mutation carriers of the Disease Network (DIAN) study (b = +0.514, P < 0.0001, Fig 6B)
Summary
Haploinsufficiency of the gene encoding progranulin (PGRN) leads to frontotemporal lobar degeneration (FTLD) with TAR DNA binding protein 43 (TDP-43) deposition (FTLD-TDP) (Baker et al, 2006; Cruts et al, 2006; Neumann et al, 2006). An AD-associated GRN variant (rs5848), which causes a decrease in PGRN levels in plasma and CSF (Rademakers et al, 2008; Nicholson et al, 2014; Morenas-Rodrıguez et al, 2015), is associated with increased CSF T-tau levels in participants of the ADNI study (Takahashi et al, 2017). Together, these results indicate a protective role of PGRN against the development of tau pathology and/or neurodegeneration
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
