Progranulin Administration Attenuates β-Amyloid Deposition in the Hippocampus of 5xFAD Mice Through Modulating BACE1 Expression and Microglial Phagocytosis

Guan, Zhangxin; Chen, Zuolong; Fu, Shumei; Dai, Linbin; Shen, Yong

doi:10.3389/fncel.2020.00260

Cited by 16 publications

(15 citation statements)

References 46 publications

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“…Microglial-specific reduction in PGRN expression has been shown to result in impaired phagocytosis, increased plaque load, and exacerbated cognitive deficits in the mouse AD models, whereas lentivirus-mediated PGRN overexpression has opposite results (Minami et al, 2014). Consistent with this result, lentivirus mediated PGRN overexpression or intrahippocampal injection of PGRN protein has been shown to reduce Aβ plaques via increasing the activity of neprilysin, a key amyloid β-degrading enzyme (Van Kampen & Kay, 2017) or through inhibiting the expression of BACE1, an enzyme involved in Aβ generation (Guan et al, 2020). However, another study has found significantly reduced diffuse Aβ plaque growth in hippocampus and cortex in aged PGRN-deficient mice using the APPswe/PS1ΔE9 (APP/PS1) mouse model (Takahashi et al, 2017).…”

Section: Introductionmentioning

confidence: 79%

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

Wong

Zhang

et al. 2021

Life Sci. Alliance

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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.

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Section: Introductionmentioning

confidence: 79%

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

Wong

Zhang

et al. 2021

Life Sci. Alliance

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“…Loss function mutations in PGRN are considered to be a risk factor for AD [ 47 ]. Previous research on the effect of PGRN on β-amyloid deposition is inconsistent [ 48 , 49 , 50 ]. In the current study, we found that β-amyloid is mainly deposited in the midbrain of Grn −/− mice, which was not observed in the age-matched WT mice ( Figure 7 ).…”

Section: Resultsmentioning

confidence: 99%

Analysis of the Biomarkers for Neurodegenerative Diseases in Aged Progranulin Deficient Mice

Zhao

Hasan

Liou

et al. 2022

IJMS

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Neurodegenerative diseases are debilitating impairments that affect millions of people worldwide and are characterized by progressive degeneration of structure and function of the central or peripheral nervous system. Effective biomarkers for neurodegenerative diseases can be used to improve the diagnostic workup in the clinic as well as facilitate the development of effective disease-modifying therapies. Progranulin (PGRN) has been reported to be involved in various neurodegenerative disorders. Hence, in the current study we systematically compared the inflammation and accumulation of typical neurodegenerative disease markers in the brain tissue between PGRN knockout (PGRN KO) and wildtype (WT) mice. We found that PGRN deficiency led to significant neuron loss as well as activation of microglia and astrocytes in aged mice. Several characteristic neurodegenerative markers, including α-synuclein, TAR DNA-binding protein 43 (TDP-43), Tau, and β-amyloid, were all accumulated in the brain of PGRN-deficient mice as compared to WT mice. Moreover, higher aggregation of lipofuscin was observed in the brain tissue of PGRN-deficient mice compared with WT mice. In addition, the autophagy was also defective in the brain of PGRN-deficient mice, indicated by the abnormal expression level of autophagy marker LC3-II. Collectively, comprehensive assays support the idea that PGRN plays an important role during the development of neurodegenerative disease, indicating that PGRN might be a useful biomarker for neurodegenerative diseases in clinical settings.

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“…Little was previously known about the role of PGRN in the nervous system, but since the discovery of PGRN genetic polymorphisms, the number of studies on the role of PGRN in the brain has increased rapidly. Studies have found that PGRN can activate microglia cells and stimulate them to engulf the toxic Aβ around them, which exerts neuroprotective effects [23]. Other studies have found that the content of PGRN in microglia cells which are around Aβ deposits increases in mice [24].…”

Section: Discussionmentioning

confidence: 99%

CSF PGRN May be Associated With Postoperative Delirium After Knee Replacement in Elderly Patients: The PNDABLE Study

Wang

Sun

et al. 2021

Preprint

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BackgroundPostoperative delirium (POD) represents a serious complication following anesthesia and surgical procedures for patients undergoing surgical intervention (1). Little is known about the mechanisms underlying similarities in the core features between postoperative delirium (POD) and progranulin (PGRN)-related cognitive disorders. We herein investigated the relationship between preoperative CSF PGRN concentration and POD occurrence in the Han Chinese patients undergoing unilateral total knee arthroplasty.MethodsWe conducted an observational, prospective, and 1:1 matched (on age older than 65, the unilateral total knee arthroplasty, American Society of Anesthesiologist’ (ASA) physical status, duration of surgery, and intraoperative bleeding) case-control study. POD cases and non-POD controls were selected from the overall cohort using Confusion Assessment Method (CAM). Delirium severity was measured by the Memorial Delirium Assessment Scale (MDAS). CSF PGRN and core biomarkers were measured by ELISA using the microplate reader. The associations of CSF PGRN levels with POD risk and CSF core biomarkers were assessed.ResultsPOD incidence was 9.7% (53/545). There were significant differences in preoperative CSF PGRN concentration between POD patients and controls (P<0.001), and CSF PGRN levels increased with age, as demonstrated by a significantly positive correlation (r=0.796, P<0.001).CSF PGRN levels to increase with CAM scores and MDAS scores, as demonstrated by significantly positive correlations (r=0.693, P<0.001; r=0.590, P<0.001). There were positive associations of CSF PGRN with T-tau (β = -0.501, P < 0.001) and P-tau (β = -0.470, P < 0.001) and negative associations of CSF PGRN with Aβ1–42 (β = -0.576, P < 0.001), Aβ1–40 (β = -0.488, P < 0.001), Aβ42/p-tau (β = -0.422, P < 0.001), and Aβ42 / T- tau (β = -0.395, P < 0.001) in POD patients. The ROC curve analysis of PGRN showed that PGRN concentrations had high diagnostic value for POD.ConclusionsCSF PGRN may be associated with the POD. Aβ pathology is associated with a decrease in CSF PGRN in the absence of tau deposition and neurodegeneration, whereas tau pathology and neurodegeneration is associated with an increase in CSF PGRN.Clinical Trial Registrationwww.clinicaltrials.gov, identifier ChiCTR2000033439.

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Progranulin Administration Attenuates β-Amyloid Deposition in the Hippocampus of 5xFAD Mice Through Modulating BACE1 Expression and Microglial Phagocytosis

Cited by 16 publications

References 46 publications

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

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

Analysis of the Biomarkers for Neurodegenerative Diseases in Aged Progranulin Deficient Mice

CSF PGRN May be Associated With Postoperative Delirium After Knee Replacement in Elderly Patients: The PNDABLE Study

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