Progranulin deficiency results in sex-dependent alterations in microglia in response to demyelination

Zhang, Tingting; Feng, Tuancheng; Wu, Kenton; Guo, Jennifer; Nana, Alissa L.; Yang, Guang; Seeley, William W.; Hu, Fenghua

doi:10.1007/s00401-023-02578-w

Cited by 6 publications

(4 citation statements)

References 95 publications

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“…5b ). Given recent reports of sex differences in microglia and other immune responses in progranulin knockout mice ( Houser et al, 2022 ; Zhang et al, 2023 ), we powered this study to compare the LPS response in male and female mice. However, we did not observe a significant sex difference in LPS response ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Regulation of extracellular progranulin in medial prefrontal cortex

Kaplelach,

Fox,

Cook

et al. 2023

Neurobiology of Disease

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Section: Resultsmentioning

confidence: 99%

Regulation of extracellular progranulin in medial prefrontal cortex

Kaplelach,

Fox,

Cook

et al. 2023

Neurobiology of Disease

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“…112 As reported, progranulin deficiency results in sex-dependent alterations in microglia, which was followed by OLs disruption. 113 In addition to their function in the form of myelination, disruption of OLs also correlates with other AD pathologies.…”

Section: Ols Also Participate In Other Ad Pathologiesmentioning

confidence: 99%

Recognizing Alzheimer's disease from perspective of oligodendrocytes: Phenomena or pathogenesis?

Wang,

Zhen,

Yang

et al. 2024

CNS Neurosci Ther

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BackgroundAccumulation of amyloid beta, tau hyperphosphorylation, and microglia activation are the three highly acknowledged pathological factors of Alzheimer's disease (AD). However, oligodendrocytes (OLs) were also widely investigated in the pathogenesis and treatment for AD.AimsWe aimed to update the regulatory targets of the differentiation and maturation of OLs, and emphasized the key role of OLs in the occurrence and treatment of AD.MethodsThis review first concluded the targets of OL differentiation and maturation with AD pathogenesis, and then advanced the key role of OLs in the pathogenesis of AD based on both clinic and basic experiments. Later, we extensively discussed the possible application of the current progress in the diagnosis and treatment of this complex disease.ResultsMolecules involving in OLs’ differentiation or maturation, including various transcriptional factors, cholesterol homeostasis regulators, and microRNAs could also participate in the pathogenesis of AD. Clinical data point towards the impairment of OLs in AD patients. Basic research further supports the central role of OLs in the regulation of AD pathologies. Additionally, classic drugs, including donepezil, edaravone, fluoxetine, and clemastine demonstrate their potential in remedying OL impairment in AD models, and new therapeutics from the perspective of OLs is constantly being developed.ConclusionsWe believe that OL dysfunction is one important pathogenesis of AD. Factors regulating OLs might be biomarkers for early diagnosis and agents stimulating OLs warrant the development of anti‐AD drugs.

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“…Increase CD68 + macrophage cell line in laser-irradiated RPE–choroid complex [ 198 ] • Age-dependent increase in Iba1 + and Cd68 + cells. Increase in Tnf , Mpeg1 , Cyba , Cybb , C4 , and Lcn2 expression in cortex, thalamus and VPM/VPL [ 201 ] • Increased serum Il-6, Il-10, and MCP1 after LPS, Decreased Listeria/Lc3 co-localization in Grn KO BMDM [ 128 ] Grn KO (Ding) Targeted deletion of exons 1–4 of Grn gene [ 99 ] • Prosaposin trafficking defects in immortalized cell lines and brain [ 35 ] • Age-dependent increase in Gpnmb and Galectin-3, primarily on microglia [ 17 ] • Increased Galectin-3 +, Plin2 +, and lipofuscin accumulation in response to demyelination in brain [ 205 ] • Increased Lamp1 +, Cathepsin D +, and lipofuscin accumulation [ 206 ] • Decreased abundance of BMP species, age-dependent increase in glucosylsphingosine and decrease in GCase activity in brain and BMDM [ 207 ] • Increased Tnf, Il-6, and iNos and decreased Il-10 after spinal cord injury [ 203 ] • Increased Tnf, Il-6, and Il-1b after LPS treatment in macrophages [ 99 ] • Increase Tnf, Il-6, and Il-1b after LPS injection, increased immune cell infiltration into lungs during LPS treatment [ 204 ] • Age-dependent increase in plasma Gpnmb ECF [ 17 ] • Increased Iba1 +, Gpnmb +, and Trem2 + staining in response to demyelination in brain [ 205 ] • Increased Iba1 +, Gfap +, and Cd68 + [ 206 ] • Sex-dependent effects in immune cells: increase in Ly6C high monocytes in blood, decrease of MHCII expression in microglia, increase in CD8 + T cells in both blood and brain, altered CD44 expression on T-cell populations [ 100 ] Grn R493X (knock-in) Knock-in of R504X Grn gene; mimics the R493X GRN mutation, positive for nonsense-mediated decay [ 153 ] • Altered ganglioside metabolism and decreased BMP levels in brain [ 82 ] • Increased cathepsin D expression, higher Lc3II/LC3I ratio in brain [ 154 ] …”

Section: Introductionmentioning

confidence: 99%

“…• Increased Galectin-3 +, Plin2 +, and lipofuscin accumulation in response to demyelination in brain [ 205 ]…”

Section: Introductionmentioning

confidence: 99%

Progranulin and GPNMB: interactions in endo-lysosome function and inflammation in neurodegenerative disease

Gillett,

Wallings,

Uriarte Huarte

et al. 2023

J Neuroinflammation

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Background Alterations in progranulin (PGRN) expression are associated with multiple neurodegenerative diseases (NDs), including frontotemporal dementia (FTD), Alzheimer’s disease (AD), Parkinson’s disease (PD), and lysosomal storage disorders (LSDs). Recently, the loss of PGRN was shown to result in endo-lysosomal system dysfunction and an age-dependent increase in the expression of another protein associated with NDs, glycoprotein non-metastatic B (GPNMB). Main body It is unclear what role GPNMB plays in the context of PGRN insufficiency and how they interact and contribute to the development or progression of NDs. This review focuses on the interplay between these two critical proteins within the context of endo-lysosomal health, immune function, and inflammation in their contribution to NDs. Short conclusion PGRN and GPNMB are interrelated proteins that regulate disease-relevant processes and may have value as therapeutic targets to delay disease progression or extend therapeutic windows.

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Progranulin deficiency results in sex-dependent alterations in microglia in response to demyelination

Cited by 6 publications

References 95 publications

Regulation of extracellular progranulin in medial prefrontal cortex

Regulation of extracellular progranulin in medial prefrontal cortex

Recognizing Alzheimer's disease from perspective of oligodendrocytes: Phenomena or pathogenesis?

Progranulin and GPNMB: interactions in endo-lysosome function and inflammation in neurodegenerative disease

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