Progranulin in neurodegenerative dementia

Wang, Xiaoming; Zeng, Peng; Fang, Ying-Yan; Zhang, Teng; Tian, Qing

doi:10.1111/jnc.15378

Cited by 26 publications

(21 citation statements)

References 226 publications

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“…39,40 Studies also have shown that PGRN is expressed by microglia and its deficiency may give birth to an aberrant increase in phagocytosis and lysosome function, 39 as well as the transition from homeostatic to disease-specific state of microglia. 41,42 Collectively, these results suggest an important role of PGRN in the modulation of neurodegeneration and neuroinflammatory diseases. Elucidation of the modulating mechanisms of PGRN in the neurodegeneration and neuroinflammation may provide new insight onto the target for the studies on prevention and treatment of these diseases.…”

Section: Discussionmentioning

confidence: 80%

Progranulin Suppressed Autoimmune Uveitis and Autoimmune Neuroinflammation by Inhibiting Th1/Th17 Cells and Promoting Treg Cells and M2 Macrophages

Wang

Zhou

et al. 2022

Neurol Neuroimmunol Neuroinflamm

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Background and ObjectivesProgranulin (PGRN) is an important immune regulatory molecule in several immune-mediated diseases. The objective of this study is to investigate the role of PGRN in uveitis and its counterpart, experimental autoimmune uveitis (EAU), and experimental autoimmune encephalomyelitis (EAE).MethodsSerum PGRN levels in patients with Behcet disease (BD) or Vogt-Koyanagi-Harada (VKH) disease and normal controls were measured by ELISA. EAE and EAU were induced in B10RIII, wild-type, and PGRN−/− mice to evaluate the effect of PGRN on the development of these 2 immune-mediated disease models. The local and systemic immunologic alterations were detected by ELISA, flow cytometry, and real-time PCR. RNA sequencing was performed to identify the hub genes and key signaling pathway.ResultsA significantly decreased PGRN expression was observed in patients with active BD and active VKH. Recombinant PGRN significantly reduced EAU severity in association with a decreased frequency of Th17 and Th1 cells. PGRN−/− mice developed an exacerbated EAU and EAE in association with strikingly increased frequency of Th1 and Th17 cells and reduced frequency of regulatory T (Treg) cells. In vitro studies revealed that rPGRN could inhibit IRBP161–180-specific Th1 and Th17 cell response and promote Treg cell expansion. It promoted non–antigen-specific Treg cell polarization from naive CD4+ T cells in association with increased STAT5 phosphorylation. Using RAN sequencing, we identified 5 shared hub genes including Tnf, Il6, Il1b, Cxcl2, and Ccl2 and the most significantly enriched MAPK and tumor necrosis factor signaling pathway in PGRN−/− EAU mice. The aggravated EAE activity in PGRN−/− mice was associated with a skew from M2 to M1 macrophages.DiscussionOur results collectively reveal an important protective role of PGRN in EAU and EAE. These studies suggest that PGRN could serve as an immunoregulatory target in the study of prevention and treatment for the Th1/Th17-mediated diseases.

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Section: Discussionmentioning

confidence: 80%

Progranulin Suppressed Autoimmune Uveitis and Autoimmune Neuroinflammation by Inhibiting Th1/Th17 Cells and Promoting Treg Cells and M2 Macrophages

Wang

Zhou

et al. 2022

Neurol Neuroimmunol Neuroinflamm

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“…It is noteworthy that the distribution of the main bioactive phytochemicals of CR focused in this study is highly specific, such as butylidenephthalide, neocnidilide, senkyunolide A, and Z-ligustilide, which are only present in 3, 6, 10, and 13 herbs, respectively, including CR (data from HERB, http://herb.ac.cn/ ) ( Fang et al, 2021 ). In stark contrast, numerous network pharmacology studies have identified quercetin (related to 341 herbs), kaempferol (related to 248 herbs), luteolin (related to 181 herbs), and β-sitosterol (related to 567 herbs), among others, as candidate phytochemicals for different diseases ( Wang Y. et al, 2021 ; Zhou et al, 2021 ). These widely distributed phytochemicals are highly unlikely to be the herb-specific active ingredients.…”

Section: Discussionmentioning

confidence: 99%

“…The clearance of physiological and pathological tau is mainly mediated by the ubiquitin proteasome system and autophagy/lysosomal degradation pathway. In AD patients, the neuronal lysosome system was dysregulated ( Sundelof et al, 2010 ; Wang X. M. et al, 2021 ; Liu et al, 2021 ; Hamano et al, 2021 ). The results of this study show that CR promotes the degradation of pathological tau mainly through the lysosome system rather than the proteasome system.…”

Section: Discussionmentioning

confidence: 99%

A Tau Pathogenesis-Based Network Pharmacology Approach for Exploring the Protections of Chuanxiong Rhizoma in Alzheimer’s Disease

Zeng

Qiu

et al. 2022

Front. Pharmacol.

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Alzheimer’s disease (AD) is the most common cause of neurodegenerative dementia and one of the top medical concerns worldwide. Currently, the approved drugs to treat AD are effective only in treating the symptoms, but do not cure or prevent AD. Although the exact causes of AD are not understood, it is recognized that tau aggregation in neurons plays a key role. Chuanxiong Rhizoma (CR) has been widely reported as effective for brain diseases such as dementia. Thus, we explored the protections of CR in AD by a tau pathogenesis–based network pharmacology approach. According to ultra-HPLC with triple quadrupole mass spectrometry data and Lipinski’s rule of five, 18 bioactive phytochemicals of CR were screened out. They were shown corresponding to 127 tau pathogenesis–related targets, among which VEGFA, IL1B, CTNNB1, JUN, ESR1, STAT3, APP, BCL2L1, PTGS2, and PPARG were identified as the core ones. We further analyzed the specific actions of CR-active phytochemicals on tau pathogenesis from the aspects of tau aggregation and tau-mediated toxicities. It was shown that neocnidilide, ferulic acid, coniferyl ferulate, levistilide A, Z-ligustilide, butylidenephthalide, and caffeic acid can be effective in reversing tau hyperphosphorylation. Neocnidilide, senkyunolide A, butylphthalide, butylidenephthalide, Z-ligustilide, and L-tryptophan may be effective in promoting lysosome-associated degradation of tau, and levistilide A, neocnidilide, ferulic acid, L-tryptophan, senkyunolide A, Z-ligustilide, and butylidenephthalide may antagonize tau-mediated impairments of intracellular transport, axon and synaptic damages, and neuron death (especially apoptosis). The present study suggests that acting on tau aggregation and tau-mediated toxicities is part of the therapeutic mechanism of CR against AD.

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“…Progranulin (PGRN) is a secreted protein that is primarily expressed in neurons and microglia in the central nervous system. It demonstrates multifunctional biological functions, including vital roles in inflammation and neurodegeneration disease ( Wang et al, 2021 ). PGRN deficiency promotes neuroinflammation, and it has been a valuable biomarker for frontotemporal lobar degeneration (FTLD).…”

Section: Introductionmentioning

confidence: 99%

Microglial Activation, Tau Pathology, and Neurodegeneration Biomarkers Predict Longitudinal Cognitive Decline in Alzheimer’s Disease Continuum

Chen

Lin

Huang

et al. 2022

Front. Aging Neurosci.

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PurposeBiomarkers used for predicting longitudinal cognitive change in Alzheimer’s disease (AD) continuum are still elusive. Tau pathology, neuroinflammation, and neurodegeneration are the leading candidate predictors. We aimed to determine these three aspects of biomarkers in cerebrospinal fluid (CSF) and plasma to predict longitudinal cognition status using Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort.Patients and MethodsA total of 430 subjects including, 96 cognitive normal (CN) with amyloid β (Aβ)-negative, 54 CN with Aβ-positive, 195 mild cognitive impairment (MCI) with Aβ-positive, and 85 AD with amyloid-positive (Aβ-positive are identified by CSF Aβ42/Aβ40 < 0.138). Aβ burden was evaluated by CSF and plasma Aβ42/Aβ40 ratio; tau pathology was evaluated by CSF and plasma phosphorylated-tau (p-tau181); microglial activation was measured by CSF soluble TREM2 (sTREM2) and progranulin (PGRN); neurodegeneration was measured by CSF and plasma t-tau and structural magnetic resonance imaging (MRI); cognition was examined annually over the subsequent 8 years using the Alzheimer’s Disease Assessment Scale Cognition 13-item scale (ADAS13) and Mini-Mental State Exam (MMSE). Linear mixed-effects models (LME) were applied to assess the correlation between biomarkers and longitudinal cognition decline, as well as their effect size on the prediction of longitudinal cognitive decline.ResultsBaseline CSF Aβ42/Aβ40 ratio was decreased in MCI and AD compared to CN, while CSF p-tau181 and t-tau increased. Baseline CSF sTREM2 and PGRN did not show any differences in MCI and AD compared to CN. Baseline brain volumes (including the hippocampal, entorhinal, middle temporal lobe, and whole-brain) decreased in MCI and AD groups. For the longitudinal study, there were significant interaction effects of CSF p-tau181 × time, plasma p-tau181 × time, CSF sTREM2 × time, and brain volumes × time, indicating CSF, and plasma p-tau181, CSF sTREM2, and brain volumes could predict longitudinal cognition deterioration rate. CSF sTREM2, CSF, and plasma p-tau181 had similar medium prediction effects, while brain volumes showed stronger effects in predicting cognition decline.ConclusionOur study reported that baseline CSF sTREM2, CSF, and plasma p-tau181, as well as structural MRI, could predict longitudinal cognitive decline in subjects with positive AD pathology. Plasma p-tau181 can be used as a relatively noninvasive reliable biomarker for AD longitudinal cognition decline prediction.

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Progranulin in neurodegenerative dementia

Cited by 26 publications

References 226 publications

Progranulin Suppressed Autoimmune Uveitis and Autoimmune Neuroinflammation by Inhibiting Th1/Th17 Cells and Promoting Treg Cells and M2 Macrophages

Progranulin Suppressed Autoimmune Uveitis and Autoimmune Neuroinflammation by Inhibiting Th1/Th17 Cells and Promoting Treg Cells and M2 Macrophages

A Tau Pathogenesis-Based Network Pharmacology Approach for Exploring the Protections of Chuanxiong Rhizoma in Alzheimer’s Disease

Microglial Activation, Tau Pathology, and Neurodegeneration Biomarkers Predict Longitudinal Cognitive Decline in Alzheimer’s Disease Continuum

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