Abstract
Neurodegenerative diseases such as Alzheimer’s disease have proven resistant to new treatments. The complexity of neurodegenerative disease mechanisms can be highlighted by accumulating evidence for a role for a growth factor, progranulin (PGRN). PGRN is a glycoprotein encoded by the GRN/Grn gene with multiple cellular functions, including neurotrophic, anti-inflammatory and lysosome regulatory properties. Mutations in the GRN gene can lead to frontotemporal lobar degeneration (FTLD), a cause of dementia, and neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Both diseases are associated with loss of PGRN function resulting, amongst other features, in enhanced microglial neuroinflammation and lysosomal dysfunction. PGRN has also been implicated in Alzheimer’s disease (AD). Unlike FTLD, increased expression of PGRN occurs in brains of human AD cases and AD model mice, particularly in activated microglia. How microglial PGRN might be involved in AD and other neurodegenerative diseases will be discussed. A unifying feature of PGRN in diseases might be its modulation of lysosomal function in neurons and microglia. Many experimental models have focused on consequences of PGRN gene deletion: however, possible outcomes of increasing PGRN on microglial inflammation and neurodegeneration will be discussed. We will also suggest directions for future studies on PGRN and microglia in relation to neurodegenerative diseases.
Highlights
Alzheimer’s disease (AD) is the major cause of cognitive decline and dementia in the elderly.New treatments aimed at removing or preventing Aβ accumulations have generally been clinically ineffective in terms of significantly preventing loss of cognition, though recent amyloid antibody therapies are showing some encouraging results in early phase trials [1,2,3]
In late-onset AD cases, higher cerebrospinal fluid (CSF) PGRN levels were associated with more advanced disease stages and cognitive impairment, and once pathology had commenced correlated with CSF levels of soluble triggering receptor expressed on myeloid cells 2 (TREM2) [76]
It has been concluded that a significant role for PGRN in neurodegenerative disease pathology is due to changes in the regulation of microglial inflammatory responses
Summary
Alzheimer’s disease (AD) is the major cause of cognitive decline and dementia in the elderly. Neuroinflammation has long been considered a pathological driver of AD pathology, though anti-inflammatory therapies have not been effective in halting cognitive decline [6]. In this context is the growth factor progranulin (PGRN), which has significant neurotrophic and anti-inflammatory properties, and appears to be expressed in increased amounts by microglia present in conditions of pathology. PGRN could could be be considered considered as as aa “brake “brake to to suppress suppress excessive excessive microglial microglial activation activation in in that the aging brain by facilitating phagocytosis and lysosomal trafficking in microglia“[10].
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.
