Microglial Progranulin: Involvement in Alzheimer’s Disease and Neurodegenerative Diseases

Mendsaikhan, Anarmaa; Tooyama, Ikuo; Walker, Douglas G.

doi:10.3390/cells8030230

Cited by 62 publications

(46 citation statements)

References 157 publications

(251 reference statements)

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“…These proteins also play a prominent role in modulating cognition and memory by promoting neuronal survival and development and by regulating synaptic plasticity [3,4,67,68,69,70]. Our data demonstrate that MG or GO, by decreasing the expression of NSE, PRGN, MMP-9 and APP, can reduce the neurotrophic properties, neuritic growth, synaptogenesis, anti-inflammatory activity, and ability of neurons to degrade Aβ, as well as modify the lysosome regulatory properties of neuronal cells [71,72,73,74]. In the brain, ANGPTL-4 is mainly expressed by reactive astrocytes but its regulation in neuronal cells is poorly described.…”

Section: Discussionmentioning

confidence: 95%

Methylglyoxal and Glyoxal as Potential Peripheral Markers for MCI Diagnosis and Their Effects on the Expression of Neurotrophic, Inflammatory and Neurodegenerative Factors in Neurons and in Neuronal Derived-Extracellular Vesicles

Haddad

Perrotte

Khedher

et al. 2019

IJMS

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Methylglyoxal (MG) and glyoxal (GO) are suggested to be associated with the development of neurodegenerative pathologies. However, their peripheral levels in relation to cognitive decline and their effects on key factors in neuronal cells are poorly investigated. The aim of this study was to determine their serum levels in MCI (mild cognitive impairment) and Alzheimer’s disease (AD) patients, to analyze their effects on the neurotrophic and inflammatory factors, on neurodegenerative markers in neuronal cells and in neuronal derived-extracellular vesicles (nEVs). Our results show that MG and GO levels in serum, determined by HPLC, were higher in MCI. ROC (receiver-operating characteristic curves) analysis showed that the levels of MG in serum have higher sensitivity to differentiate MCI from controls but not from AD. Meanwhile, serum GO levels differentiate MCI from control and AD groups. Cells and nEVs levels of BDNF, PRGN, NSE, APP, MMP-9, ANGPTL-4, LCN2, PTX2, S100B, RAGE, Aβ peptide, pTau T181 and alpha-synuclein were quantified by luminex assay. Treatment of neuronal cells with MG or GO reduced the cellular levels of NSE, PRGN, APP, MMP-9 and ANGPTL-4 and the nEVs levels of BDNF, PRGN and LCN2. Our findings suggest that targeting MG and GO may be a promising therapeutic strategy to prevent or delay the progression of AD.

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Section: Discussionmentioning

confidence: 95%

Methylglyoxal and Glyoxal as Potential Peripheral Markers for MCI Diagnosis and Their Effects on the Expression of Neurotrophic, Inflammatory and Neurodegenerative Factors in Neurons and in Neuronal Derived-Extracellular Vesicles

Haddad

Perrotte

Khedher

et al. 2019

IJMS

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“…Heterozygous mutation of the GRN gene is the major cause of FTD-TDP, which is a subtype of frontotemporal dementia (FTD) characterized by ubiquitinated and fragmented TAR-DNA binding protein-43 (TDP-43) [29, 30]. Meanwhile, the polymorphism of Grn gene is associated with the late-onset Alzheimer’s disease [31] and exogenous addition of PGRN can protect against amyloid beta deposition and toxicity in an Alzheimer’s animal model [32, 33]. Besides neurodegenerative diseases, PGRN also acts as a potential therapeutic target for neurological injuries, such as subarachnoid hemorrhage (SAH) [34], acute ischemic stroke [35], and neural injury [20] following spinal contusion.…”

Section: Discussionmentioning

confidence: 99%

Progranulin deficiency exacerbates spinal cord injury by promoting neuroinflammation and cell apoptosis in mice

Wang

Zhang

Ndong

et al. 2019

J Neuroinflammation

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PurposeSpinal cord injury (SCI) often results in significant and catastrophic dysfunction and disability and imposes a huge economic burden on society. This study aimed to determine whether progranulin (PGRN) plays a role in the progressive damage following SCI and evaluate the potential for development of a PGRN derivative as a new therapeutic target in SCI.MethodsPGRN-deficient (Gr−/−) and wild-type (WT) littermate mice were subjected to SCI using a weight-drop technique. Local PGRN expression following injury was evaluated by Western blotting and immunofluorescence. Basso Mouse Scale (BMS), inclined grid walking test, and inclined plane test were conducted at indicated time points to assess neurological recovery. Inflammation and apoptosis were examined by histology (Hematoxylin and Eosin (H&E) staining and Nissl staining, TUNEL assays, and immunofluorescence), Western blotting (from whole tissue protein for iNOS/p-p65/Bax/Bcl-2), and ex vivo ELISA (for TNFα/IL-1β/IL-6/IL-10). To identify the prophylactic and therapeutic potential of targeting PGRN, a PGRN derived small protein, Atsttrin, was conjugated to PLGA-PEG-PLGA thermosensitive hydrogel and injected into intrathecal space prior to SCI. BMS was recorded for neurological recovery and Western blotting was applied to detect the inflammatory and apoptotic proteins.ResultsAfter SCI, PGRN was highly expressed in activated macrophage/microglia and peaked at day 7 post-injury. Grn−/− mice showed a delayed neurological recovery after SCI at day 21, 28, 35, and 42 post-injury relative to WT controls. Histology, TUNEL assay, immunofluorescence, Western blotting, and ELISA all indicated that Grn−/− mice manifested uncontrolled and expanded inflammation and apoptosis. Administration of control-released Atsttrin could improve the neurological recovery and the pro-inflammatory/pro-apoptotic effect of PGRN deficiency.ConclusionPGRN deficiency exacerbates SCI by promoting neuroinflammation and cellular apoptosis, which can be alleviated by Atsttrin. Collectively, our data provide novel evidence of using PGRN derivatives as a promising therapeutic approach to improve the functional recovery for patients with spinal cord injury.

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“…PGRN is a widely distributed pleiotropic protein that consists of seven and half cysteine-rich repeats (Mendsaikhan et al, 2019). In the brain, PGRN is secreted from microglia and acts as a neurotrophic factor, regulating a diverse range of cellular functions including cell proliferation, neuron survival, cell migration, neurite extension, lysosomal function, and antiinflammatory responses (Toh et al, 2011;Kao et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Anti-sortilin1 Antibody Up-Regulates Progranulin via Sortilin1 Down-Regulation

et al. 2020

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Progranulin (PGRN) haploinsufficiency associated with loss-of-function mutations in the granulin gene causes frontotemporal dementia (FTD). This suggests that increasing PGRN levels could have promising therapeutic implications for patients carrying GRN mutations. In this study, we explored the therapeutic potential of sortilin1 (SORT1), a clearance receptor of PGRN, by generating and characterizing monoclonal antibodies against SORT1. Anti-SORT1 monoclonal antibodies were generated by immunizing Sort1 knockout mice with SORT1 protein. The antibodies were classified into 7 epitope bins based on their competitive binding to the SORT1 protein and further defined by epitope bin-dependent characteristics, including SORT1-PGRN blocking, SORT1 down-regulation, and binding to human and mouse SORT1. We identified a positive correlation between PGRN up-regulation and SORT1 down-regulation. Furthermore, we also characterized K1-67 antibody via SORT1 down-regulation and binding to mouse SORT1 in vivo and confirmed that K1-67 significantly up-regulated PGRN levels in plasma and brain interstitial fluid of mice. These data indicate that SORT1 down-regulation is a key mechanism in increasing PGRN levels via anti-SORT1 antibodies and suggest that SORT1 is a potential target to correct PGRN reduction, such as that in patients with FTD caused by GRN mutation.

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Microglial Progranulin: Involvement in Alzheimer’s Disease and Neurodegenerative Diseases

Cited by 62 publications

References 157 publications

Methylglyoxal and Glyoxal as Potential Peripheral Markers for MCI Diagnosis and Their Effects on the Expression of Neurotrophic, Inflammatory and Neurodegenerative Factors in Neurons and in Neuronal Derived-Extracellular Vesicles

Methylglyoxal and Glyoxal as Potential Peripheral Markers for MCI Diagnosis and Their Effects on the Expression of Neurotrophic, Inflammatory and Neurodegenerative Factors in Neurons and in Neuronal Derived-Extracellular Vesicles

Progranulin deficiency exacerbates spinal cord injury by promoting neuroinflammation and cell apoptosis in mice

Anti-sortilin1 Antibody Up-Regulates Progranulin via Sortilin1 Down-Regulation

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