-
Frontiers in Immunology 2020Cancer-associated fibroblasts (CAFs) were associated with tumor progression in the tumor microenvironment (TME). However, their immunosuppressive roles in protecting...
Cancer-associated fibroblasts (CAFs) were associated with tumor progression in the tumor microenvironment (TME). However, their immunosuppressive roles in protecting cancer cells from the attack by cytotoxic T lymphocytes (CTLs) are not fully clear. In this study, we investigated whether and how CAFs regulate tumor-infiltrating lymphocytes as well as their role in tumor immunosuppression. Eighty-three cases of ovarian cancer and 10 controls were analyzed for CAFs and CD8+ tumor-infiltrating lymphocytes by gene array and immunohistochemistry. We evaluated presenilin 1 (PS1) expression in CAFs, CTL penetration, tumor burden, dendritic cell function, and migration of tumor-infiltrating lymphocytes and their function and after silencing PS1. In addition, the pathway via which PS1 affects the TME was also evaluated. PS1 was highly expressed in CAFs, and its silencing significantly promoted CD8+ CTL proliferation and penetration in multiple ovarian models ( < 0.05), resulting in tumor regression and growth inhibition. Interleukin (IL)-1β was identified as a major immune inhibitor in the TME, and it was significantly decreased after PS1 silencing ( < 0.05), which was regulated by the WNT/β-catenin pathway. It was also showed that high expression of IL-1β in CAFs inhibits CTL penetration significantly ( < 0.05). Highly expressed PS1 in CAFs plays a crucial role in regulating tumor-infiltrating lymphocyte populations in the TME via the WNT/β-catenin pathway. Targeting PS1 may retrieve functional CTLs in the TME and improve the efficacy of current immunotherapies.
Topics: Animals; Cancer-Associated Fibroblasts; Cell Line, Tumor; Disease Models, Animal; Female; Gene Expression Regulation, Neoplastic; Humans; Lymphocytes, Tumor-Infiltrating; Mice; Mice, Inbred C57BL; Ovarian Neoplasms; Presenilin-1; T-Lymphocytes, Cytotoxic; Tumor Microenvironment; Wnt Signaling Pathway
PubMed: 32587587
DOI: 10.3389/fimmu.2020.00999 -
Cell Reports Nov 2023During the past two decades, induced pluripotent stem cells (iPSCs) have been widely used to study human neural development and disease. Especially in the field of...
During the past two decades, induced pluripotent stem cells (iPSCs) have been widely used to study human neural development and disease. Especially in the field of Alzheimer's disease (AD), remarkable effort has been put into investigating molecular mechanisms behind this disease. Then, with the advent of 3D neuronal cultures and cerebral organoids (COs), several studies have demonstrated that this model can adequately mimic familial and sporadic AD. Therefore, we created an AD-CO model using iPSCs derived from patients with familial AD forms and explored early events and the progression of AD pathogenesis. Our study demonstrated that COs derived from three AD-iPSC lines with PSEN1(A246E) or PSEN2(N141I) mutations developed the AD-specific markers in vitro, yet they also uncover tissue patterning defects and altered development. These findings are complemented by single-cell sequencing data confirming this observation and uncovering that neurons in AD-COs likely differentiate prematurely.
Topics: Humans; Alzheimer Disease; Induced Pluripotent Stem Cells; Mutation; Neurons; Organoids; Presenilin-1; Presenilin-2
PubMed: 37864790
DOI: 10.1016/j.celrep.2023.113310 -
Biochemistry Jul 2019γ-Secretase is a membrane-embedded protease complex, with presenilin as the catalytic component containing two transmembrane aspartates in the active site. With more...
γ-Secretase is a membrane-embedded protease complex, with presenilin as the catalytic component containing two transmembrane aspartates in the active site. With more than 90 known substrates, the γ-secretase complex is considered "the proteasome of the membrane", with central roles in biology and medicine. The protease carries out hydrolysis within the lipid bilayer to cleave the transmembrane domain of the substrate multiple times before releasing secreted products. For many years, elucidation of γ-secretase structure and function largely relied on small-molecule probes and mutagenesis. Recently, however, advances in cryo-electron microscopy have led to the first detailed structures of the protease complex. Two new reports of structures of γ-secretase bound to membrane protein substrates provide great insight into the nature of substrate recognition and how Alzheimer's disease-causing mutations in presenilin might alter substrate binding and processing. These new structures offer a powerful platform for elucidating enzyme mechanisms, deciphering effects of disease-causing mutations, and advancing Alzheimer's disease drug discovery.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Animals; Cell Membrane; Cryoelectron Microscopy; Humans; Hydrolysis; Lipid Bilayers; Models, Molecular; Mutagenesis; Presenilin-1; Protein Conformation
PubMed: 31198028
DOI: 10.1021/acs.biochem.9b00401 -
International Journal of Molecular... May 2024Presenilin proteins (PS1 and PS2) represent the catalytic subunit of γ-secretase and play a critical role in the generation of the amyloid β (Aβ) peptide and the...
Presenilin proteins (PS1 and PS2) represent the catalytic subunit of γ-secretase and play a critical role in the generation of the amyloid β (Aβ) peptide and the pathogenesis of Alzheimer disease (AD). However, PS proteins also exert multiple functions beyond Aβ generation. In this study, we examine the individual roles of PS1 and PS2 in cellular cholesterol metabolism. Deletion of PS1 or PS2 in mouse models led to cholesterol accumulation in cerebral neurons. Cholesterol accumulation was also observed in the lysosomes of embryonic fibroblasts from Psen1-knockout (PS1-KO) and (PS2-KO) mice and was associated with decreased expression of the Niemann-Pick type C1 (NPC1) protein involved in intracellular cholesterol transport in late endosomal/lysosomal compartments. Mass spectrometry and complementary biochemical analyses also revealed abnormal N-glycosylation of NPC1 and several other membrane proteins in PS1-KO and PS2-KO cells. Interestingly, pharmacological inhibition of N-glycosylation resulted in intracellular cholesterol accumulation prominently in lysosomes and decreased NPC1, thereby resembling the changes in PS1-KO and PS2-KO cells. In turn, treatment of PS1-KO and PS2-KO mouse embryonic fibroblasts (MEFs) with the chaperone inducer arimoclomol partially normalized NPC1 expression and rescued lysosomal cholesterol accumulation. Additionally, the intracellular cholesterol accumulation in PS1-KO and PS2-KO MEFs was prevented by overexpression of NPC1. Collectively, these data indicate that a loss of PS function results in impaired protein N-glycosylation, which eventually causes decreased expression of NPC1 and intracellular cholesterol accumulation. This mechanism could contribute to the neurodegeneration observed in PS KO mice and potentially to the pathogenesis of AD.
Topics: Animals; Mice; Alzheimer Disease; Cholesterol; Fibroblasts; Glycosylation; Intracellular Signaling Peptides and Proteins; Lysosomes; Mice, Knockout; Neurons; Niemann-Pick C1 Protein; Presenilin-1; Presenilin-2
PubMed: 38791456
DOI: 10.3390/ijms25105417 -
Journal of Immunology (Baltimore, Md. :... Oct 2022Peripheral immune cell infiltration into the brain is a prominent feature in aging and various neurodegenerative diseases such as Alzheimer's disease (AD). As AD...
Peripheral immune cell infiltration into the brain is a prominent feature in aging and various neurodegenerative diseases such as Alzheimer's disease (AD). As AD progresses, CD8 T cells infiltrate into the brain parenchyma, where they tightly associate with neurons and microglia. The functional properties of CD8 T cells in the brain are largely unknown. To gain further insights into the putative functions of CD8 T cells in the brain, we explored and compared the transcriptomic profile of CD8 T cells isolated from the brain and blood of transgenic AD (APPswe/PSEN1dE9, line 85 [APP-PS1]) and age-matched wild-type (WT) mice. Brain CD8 T cells of APP-PS1 and WT animals had similar transcriptomic profiles and substantially differed from blood circulating CD8 T cells. The gene signature of brain CD8 T cells identified them as tissue-resident memory (Trm) T cells. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analysis on the significantly upregulated genes revealed overrepresentation of biological processes involved in IFN-β signaling and the response to viral infections. Furthermore, brain CD8 T cells of APP-PS1 and aged WT mice showed similar differentially regulated genes as brain Trm CD8 T cells in mouse models with acute virus infection, chronic parasite infection, and tumor growth. In conclusion, our profiling of brain CD8 T cells suggests that in AD, these cells exhibit similar adaptive immune responses as in other inflammatory diseases of the CNS, potentially opening the door for immunotherapy in AD.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Brain; CD8-Positive T-Lymphocytes; Disease Models, Animal; Memory T Cells; Mice; Mice, Inbred C57BL; Mice, Transgenic; Presenilin-1; Transcriptome
PubMed: 36165202
DOI: 10.4049/jimmunol.2100737 -
The International Journal of... Sep 2023Alzheimer disease (AD) and depression often cooccur, and inhibition of phosphodiesterase-4 (PDE4) has been shown to ameliorate neurodegenerative illness. Therefore, we...
Rolipram Ameliorates Memory Deficits and Depression-Like Behavior in APP/PS1/tau Triple Transgenic Mice: Involvement of Neuroinflammation and Apoptosis via cAMP Signaling.
BACKGROUND
Alzheimer disease (AD) and depression often cooccur, and inhibition of phosphodiesterase-4 (PDE4) has been shown to ameliorate neurodegenerative illness. Therefore, we explored whether PDE4 inhibitor rolipram might also improve the symptoms of comorbid AD and depression.
METHODS
APP/PS1/tau mice (10 months old) were treated with or without daily i.p. injections of rolipram for 10 days. The animal groups were compared in behavioral tests related to learning, memory, anxiety, and depression. Neurochemical measures were conducted to explore the underlying mechanism of rolipram.
RESULTS
Rolipram attenuated cognitive decline as well as anxiety- and depression-like behaviors. These benefits were attributed at least partly to the downregulation of amyloid-β, Amyloid precursor protein (APP), and Presenilin 1 (PS1); lower tau phosphorylation; greater neuronal survival; and normalized glial cell function following rolipram treatment. In addition, rolipram upregulated B-cell lymphoma-2 (Bcl-2) and downregulated Bcl-2-associated X protein (Bax) to reduce apoptosis; it also downregulated interleukin-1β, interleukin-6, and tumor necrosis factor-α to restrain neuroinflammation. Furthermore, rolipram increased cAMP, PKA, 26S proteasome, EPAC2, and phosphorylation of ERK1/2 while decreasing EPAC1.
CONCLUSIONS
Rolipram may mitigate cognitive deficits and depression-like behavior by reducing amyloid-β pathology, tau phosphorylation, neuroinflammation, and apoptosis. These effects may be mediated by stimulating cAMP/PKA/26S and cAMP/exchange protein directly activated by cAMP (EPAC)/ERK signaling pathways. This study suggests that PDE4 inhibitor rolipram can be an effective target for treatment of comorbid AD and depression.
Topics: Mice; Animals; Amyloid beta-Protein Precursor; Rolipram; Mice, Transgenic; Phosphodiesterase 4 Inhibitors; Neuroinflammatory Diseases; Presenilin-1; Depression; Alzheimer Disease; Amyloid beta-Peptides; Memory Disorders; Apoptosis; Disease Models, Animal
PubMed: 37490542
DOI: 10.1093/ijnp/pyad042 -
Cellular and Molecular Life Sciences :... Aug 2019Alzheimer's Disease (AD) is the sixth-leading cause of death in industrialized countries. Neurotoxic amyloid-β (Aβ) plaques are one of the pathological hallmarks in AD... (Review)
Review
Alzheimer's Disease (AD) is the sixth-leading cause of death in industrialized countries. Neurotoxic amyloid-β (Aβ) plaques are one of the pathological hallmarks in AD patient brains. Aβ accumulates in the brain upon sequential, proteolytic processing of the amyloid precursor protein (APP) by β- and γ-secretases. However, so far disease-modifying drugs targeting β- and γ-secretase pathways seeking a decrease in the production of toxic Aβ peptides have failed in clinics. It has been demonstrated that the metalloproteinase meprin β acts as an alternative β-secretase, capable of generating truncated Aβ peptides that have been described to be increased in AD patients. This indicates an important β-site cleaving enzyme 1 (BACE-1)-independent contribution of the metalloprotease meprin β within the amyloidogenic pathway and may lead to novel drug targeting avenues. However, meprin β itself is embedded in a complex regulatory network. Remarkably, the anti-amyloidogenic α-secretase a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) is a direct competitor for APP at the cell surface, but also a sheddase of inactive pro-meprin β. Overall, we highlight the current cellular, molecular and structural understanding of meprin β as alternative β-secretase within the complex protease web, regulating APP processing in health and disease.
Topics: ADAM10 Protein; Alzheimer Disease; Amyloid beta-Peptides; Humans; Membrane Proteins; Metalloendopeptidases; Presenilin-1; Proteolysis; Serine Endopeptidases
PubMed: 31201463
DOI: 10.1007/s00018-019-03179-1 -
International Journal of Molecular... May 2021Perinatal asphyxia is mainly a brain disease leading to the development of neurodegeneration, in which a number of peripheral lesions have been identified; however,...
Perinatal asphyxia is mainly a brain disease leading to the development of neurodegeneration, in which a number of peripheral lesions have been identified; however, little is known about the expression of key genes involved in amyloid production by peripheral cells, such as lymphocytes, during the development of hypoxic-ischemic encephalopathy. We analyzed the gene expression of the , , and and by RT-PCR in the lymphocytes of post-asphyxia and control neonates. In all examined periods after asphyxia, decreased expression of the genes of the , and was noted in lymphocytes. Conversely, expression of and genes decreased on days 1-7 and 8-14 but increased after survival for more than 15 days. We believe that the expression of genes in lymphocytes could be a potential biomarker to determine the severity of the post-asphyxia neurodegeneration or to identify the underlying factors for brain neurodegeneration and get information about the time they occurred. This appears to be the first worldwide data on the role of the and genes associated with Alzheimer's disease in the dysregulation of neonatal lymphocytes after perinatal asphyxia.
Topics: Asphyxia; Case-Control Studies; Female; Gene Expression Regulation; Humans; Infant, Newborn; Lymphocytes; Male; Presenilin-1; Presenilin-2
PubMed: 34067945
DOI: 10.3390/ijms22105140 -
British Journal of Pharmacology Oct 2022Notch1 activation mediated by γ-secretase is critical for angiogenesis. GeneCards database predicted that Caspase-4 (CASP4, with murine ortholog CASP11) interacts with...
BACKGROUND AND PURPOSE
Notch1 activation mediated by γ-secretase is critical for angiogenesis. GeneCards database predicted that Caspase-4 (CASP4, with murine ortholog CASP11) interacts with presenilin-1, the catalytic core of γ-secretase. Therefore, we investigated the role of CASP4/11 in angiogenesis.
EXPERIMENTAL APPROACH
In vivo, we studied the role of Casp11 in several angiogenesis mouse models using Casp11 wild-type and knockout mice. In vitro, we detected the effects of CASP4 on endothelial functions and Notch signalling by depleting or overexpressing CASP4 in human umbilical vein endothelial cells (HUVECs). The functional domain responsible for the binding of CASP4 and presenilin-1 was detected by mutagenesis and co-immunoprecipitation.
KEY RESULTS
Casp11 deficiency impaired adult angiogenesis in ischaemic hindlimbs, melanoma xenografts and Matrigel plugs, but not the developmental angiogenesis of retina. Bone marrow transplantation revealed that the pro-angiogenic effect depended on CASP11 derived from non-haematopoietic cells. CASP4 expression was induced by inflammatory factors and CASP4 knockdown decreased cell viability, proliferation, migration and tube formation in HUVECs. Mechanistically, CASP4/11 deficiency increased Notch1 activation in vivo and in vitro, while CASP4 overexpression repressed Notch1 signalling in HUVECs. Moreover, CASP4 knockdown increased γ-secretase activity. The γ-Secretase inhibitor DAPT restored the effects of CASP4 siRNA on Notch1 activation and angiogenesis in HUVECs. Notably, the catalytic activity of CASP4/11 was dispensable. CASP4 directly interacted with presenilin-1 through the caspase recruitment domain (CARD).
CONCLUSIONS AND IMPLICATIONS
These findings reveal a critical role of CASP4/11 in adult angiogenesis and make this molecule a promising therapeutic target for angiogenesis-related diseases in the future.
Topics: Amyloid Precursor Protein Secretases; Animals; Caspases; Caspases, Initiator; Human Umbilical Vein Endothelial Cells; Humans; Mice; Mice, Knockout; Neovascularization, Pathologic; Presenilin-1; RNA, Small Interfering; Receptor, Notch1; Receptors, Notch
PubMed: 35737588
DOI: 10.1111/bph.15904 -
Nutrients Oct 2023The deterioration of brain glucose metabolism predates the clinical onset of Alzheimer's disease (AD). Medium-chain triglycerides (MCTs) and docosahexaenoic acid (DHA)...
Supplementation of Medium-Chain Triglycerides Combined with Docosahexaenoic Acid Inhibits Amyloid Beta Protein Deposition by Improving Brain Glucose Metabolism in APP/PS1 Mice.
The deterioration of brain glucose metabolism predates the clinical onset of Alzheimer's disease (AD). Medium-chain triglycerides (MCTs) and docosahexaenoic acid (DHA) positively improve brain glucose metabolism and decrease the expression of AD-related proteins. However, the effects of the combined intervention are unclear. The present study explored the effects of the supplementation of MCTs combined with DHA in improving brain glucose metabolism and decreasing AD-related protein expression levels in APP/PS1 mice. The mice were assigned into four dietary treatment groups: the control group, MCTs group, DHA group, and MCTs + DHA group. The corresponding diet of the respective groups was fed to mice from the age of 3 to 11 months. The results showed that the supplementation of MCTs combined with DHA could increase serum octanoic acid (C8:0), decanoic acid (C10:0), DHA, and β-hydroxybutyrate (β-HB) levels; improve glucose metabolism; and reduce nerve cell apoptosis in the brain. Moreover, it also aided with decreasing the expression levels of amyloid beta protein (Aβ), amyloid precursor protein (APP), β-site APP cleaving enzyme-1 (BACE1), and presenilin-1 (PS1) in the brain. Furthermore, the supplementation of MCTs + DHA was significantly more beneficial than that of MCTs or DHA alone. In conclusion, the supplementation of MCTs combined with DHA could improve energy metabolism in the brain of APP/PS1 mice, thus decreasing nerve cell apoptosis and inhibiting the expression of Aβ.
Topics: Mice; Animals; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Docosahexaenoic Acids; Presenilin-1; Mice, Transgenic; Aspartic Acid Endopeptidases; Disease Models, Animal; Alzheimer Disease; Brain; Dietary Supplements; Triglycerides
PubMed: 37836528
DOI: 10.3390/nu15194244