scholarly journals Inflammation and the pathophysiology of Alzheimer's disease

2000 ◽  
Vol 2 (3) ◽  
pp. 233-239
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Chronic Inflammatory Response ◽  
Immune Effector ◽  
Effector Cells ◽  
Ongoing Work ◽  
Immune Effector Cells ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
The Brain

There is increasing evidence that a chronic inflammatory response in the brain in Alzheimer's disease (AD) ultimately leads to neuronal injury and cognitive decline. Microglia, the primary immune effector cells of the brain, are thought to be key to this process. This paper discusses the evidence for inflammation in AD, and describes the mechanism whereby microglia generate neurotoxic cytokines, reactive oxygen species, and nitric oxide. Evidence that the cytokine macrophage colony-stimulating factor (M-CSF) is an important cofactor in microglial activation in AD is presented. Ongoing work using organotypic hippocampal expiant cultures to model the inflammatory process in the AD brain is also discussed. Potential avenues for therapeutic intervention are outlined.

The Role of Microglia in Sporadic Alzheimer’s Disease

2021 ◽  
Vol 79 (3) ◽  
pp. 961-968
Author(s):  
Wolfgang J. Streit ◽  
Habibeh Khoshbouei ◽  
Ingo Bechmann
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Genetic Mutations ◽  
Sporadic Alzheimer’S Disease ◽  
Immune Effector ◽  
Effector Cells ◽  
Immune Effector Cells ◽  
Amyloid Cascade

Microglia constitute the brain’s immune system and their involvement in Alzheimer’s disease has been discussed. Commonly, and in line with the amyloid/neuroinflammation cascade hypothesis, microglia have been portrayed as potentially dangerous immune effector cells thought to be overactivated by amyloid and producing neurotoxic inflammatory mediators that lead to neurofibrillary degeneration. We disagree with this theory and offer as an alternative the microglial dysfunction theory stating that microglia become impaired in their normally neuroprotective roles because of aging, i.e., they become senescent and aging neurons degenerate because they lack the needed microglial support for their survival. Thus, while the amyloid cascade theory relies primarily on genetic data, the dysfunction theory incorporates aging as a critical etiological factor. Aging is the greatest risk factor for the sporadic (late-onset) and most common form of Alzheimer’s disease, where fully penetrant genetic mutations are absent. In this review, we lay out and discuss the human evidence that supports senescent microglial dysfunction and conflicts with the amyloid/neuroinflammation idea.

scholarly journals Intracerebral GM-CSF contributes to transendothelial monocyte migration in APP/PS1 Alzheimer’s disease mice

2016 ◽  
Vol 36 (11) ◽  
pp. 1978-1991 ◽  
Author(s):  
De S Shang ◽  
Yi M Yang ◽  
Hu Zhang ◽  
Li Tian ◽  
Jiu S Jiang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Colony Stimulating Factor ◽  
Blood Brain ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
The Brain ◽  
Stimulating Factor

Although tight junctions between human brain microvascular endothelial cells in the blood–brain barrier prevent molecules or cells in the bloodstream from entering the brain, in Alzheimer’s disease, peripheral blood monocytes can “open” these tight junctions and trigger subsequent transendothelial migration. However, the mechanism underlying this migration is unclear. Here, we found that the CSF2RB, but not CSF2RA, subunit of the granulocyte-macrophage colony-stimulating factor receptor was overexpressed on monocytes from Alzheimer’s disease patients. CSF2RB contributes to granulocyte-macrophage colony-stimulating factor-induced transendothelial monocyte migration. Granulocyte-macrophage colony-stimulating factor triggers human brain microvascular endothelial cells monolayer tight junction disassembly by downregulating ZO-1 expression via transcription modulation and claudin-5 expression via the ubiquitination pathway. Interestingly, intracerebral granulocyte-macrophage colony-stimulating factor blockade abolished the increased monocyte infiltration in the brains of APP/PS1 Alzheimer’s disease model mice. Our results suggest that in Alzheimer’s disease patients, high granulocyte-macrophage colony-stimulating factor levels in the brain parenchyma and cerebrospinal fluid induced blood–brain barrier opening, facilitating the infiltration of CSF2RB-expressing peripheral monocytes across blood–brain barrier and into the brain. CSF2RB might be useful as an Alzheimer’s disease biomarker. Thus, our findings will help to understand the mechanism of monocyte infiltration in Alzheimer’s disease pathogenesis.

scholarly journals The Role of the Innate Immune System in Alzheimer’s Disease and Frontotemporal Lobar Degeneration: An Eye on Microglia

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Elisa Ridolfi ◽  
Cinzia Barone ◽  
Elio Scarpini ◽  
Daniela Galimberti
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Frontotemporal Lobar Degeneration ◽  
Environmental Changes ◽  
Current Evidence ◽  
Neuronal Function ◽  
Immune Effector ◽  
Effector Cells ◽  
The Central Nervous System

In the last few years, genetic and biomolecular mechanisms at the basis of Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) have been unraveled. A key role is played by microglia, which represent the immune effector cells in the central nervous system (CNS). They are extremely sensitive to the environmental changes in the brain and are activated in response to several pathologic events within the CNS, including altered neuronal function, infection, injury, and inflammation. While short-term microglial activity has generally a neuroprotective role, chronic activation has been implicated in the pathogenesis of neurodegenerative disorders, including AD and FTLD. In this framework, the purpose of this review is to give an overview of clinical features, genetics, and novel discoveries on biomolecular pathogenic mechanisms at the basis of these two neurodegenerative diseases and to outline current evidence regarding the role played by activated microglia in their pathogenesis.

Phase II trial of pembrolizumab (PEM) plus granulocyte macrophage colony stimulating factor (GM-CSF) in advanced biliary cancers (ABC).

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 386-386 ◽  
Author(s):  
Robin Kate Kelley ◽  
Emily Mitchell ◽  
Spencer Behr ◽  
Jimmy Hwang ◽  
Bridget Keenan ◽  
...  
Keyword(s):  
Immune Cell ◽  
Progression Free Survival ◽  
Immune Effector ◽  
Effector Cells ◽  
Gm Csf ◽  
Phase 2 Trial ◽  
Best Response ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stage 1

386 Background: The efficacy of immune checkpoint inhibition (CPI) has not been established in ABC. GM-CSF modulates immune effector cells and has demonstrated safety and improved survival (OS) in combination with ipilimumab in melanoma. This phase 2 trial aims to evaluate the efficacy and safety of PEM in combination with GM-CSF in ABC. Methods: Design: Simon’s 2-stage. Key eligibility: ABC with progression/intolerance on ≥ 1 standard therapy, no prior CPI, bilirubin ≤1.5xULN. Treatment: PEM 200 mg IV Q21 days plus 2 cycles of GM-CSF 250 µg SC D1-14 Q21 days in cycles 2 and 3 (Stage 1 Safety Cohort) or in cycles 1 and 2 (Stage 2). Endpoints: 1◦: Progression-free survival at 6 months (PFS6) with H0 25% vs. H1 50%. Key 2◦: Safety, overall response rate (ORR) and duration (DOR), OS, PD-L1 expression. Exploratory: PBMC and tumor immune cell profiles, tumor genotype, microsatellite (in)stability (MSI or MSS). Results: Accrual has completed with 27 patients (pts) enrolled 5/2016-6/2017: F/M 13/14; median age 61 (range 37-77); intrahepatic 19 (70%), extrahepatic 7 (26%), mixed 1 (4%) cholangiocarcinoma; stage IVA/B 85%, II/III 15%; median prior therapies 2 (range 1-6). Adverse events (AE): Related grade(Gr) ≥3 AE occurred in 4/27 (15%) pts including immune-related (ir)AE of Gr4 diabetes mellitus and Gr3 thrombocytopenia in 1 pt each. Gr≤2 irAE in ≥5% were: arthralgia (33%), dry eye/mouth (15%), hyperthyroid/thyroiditis (15%), hypothyroid (15%), neuropathy (11%), rash (11%), and adrenal insufficiency (7%). Steroids were required in 3/27 (11%) pts. Disposition: 19 pts removed for PD, 1 for Gr2 irAE; 7 pts remain active on treatment. Median time on treatment: 6 cycles (range 2-22+). Best response by RECIST 1.1: Partial response (PR) in 5/24 (21%) evaluable pts (1 MSI, 4 MSS); minor regression and ≥50% CA 19-9 decline in 2 additional MSS pts for 11+ and 16+ months. PBMC analyses show changes in expression of activating and inhibitory markers including PD-1 on various immune cell populations. Conclusions: PEM plus induction GM-CSF is safe and tolerable in ABC. Durable radiographic and tumor marker responses including MSS pts warrant further study. PFS6, OS, and correlative analyses are ongoing. Clinical trial information: NCT02703714.

Amyloid β Protein Deposition in Osteopetrotic (op/op) Mice Is Reduced by Injections of Macrophage Colony Stimulating Factor

2005 ◽  
Vol 33 (6) ◽  
pp. 654-660 ◽  
Author(s):  
T Kawata ◽  
K Tsutsui ◽  
S Kohno ◽  
M Kaku ◽  
T Fujita ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Microglial Cell ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Colony Stimulating Factor ◽  
Β Protein ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

The deposition of amyloid β (Aβ) protein is a neuropathological change that characterizes Alzheimer's disease. Animals with the osteopetrosis (op/op) mutation suffer from a general skeletal sclerosis, a significantly reduced number of macrophages and osteoclasts in various tissues, and have no systemic macrophage colony stimulating factor (M-CSF). This study examined the effect that M-CSF injections had on Aβ deposition and microglial cell distribution in the brains of normal and op/op mice. Aβ-positive plaques were detected in the cerebral cortex of op/op mice, but not in normal mice. M-CSF reduced the numbers of Aβ-positive plaques in op/op mice. The microglial cell population was reduced in op/op mice compared with normal mice, and M-CSF increased the numbers to 65.8% of that observed in normal mice. Our results suggest that a clearer understanding of the role that microglial cells play in Aβ deposition may help determine the mechanisms involved in the pathogenesis of Alzheimer's disease.

Interleukin-2 and Granulocyte-Macrophage Colony Stimulating Factor Is an Alternative to Donor Lymphocyte Infusion for Relapse after Allogeneic Stem Cell Transplantation and Is Associated with Increase Immune Effector Cells and Polarization to Type 2 Dendritic Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1647-1647
Author(s):  
Carlos R. Bachier ◽  
Paul Shaughnessy ◽  
Brad Smith2 ◽  
Richard Salinas ◽  
Charles F. LeMaistre
Keyword(s):  
Stem Cell ◽  
Immune Activation ◽  
Interleukin 2 ◽  
Donor Lymphocyte Infusion ◽  
P Value ◽  
Immune Effector ◽  
Effector Cells ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony

Abstract Donor lymphocyte infusion (DLI) is use for relapse after allogeneic stem cell transplant (ASCT). Immune activation with cytokines maybe an alternative to DLI. We administered Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) and Interleukin-2 (IL-2) at the time of relapse after ASCT in patients (pts) with hematologic malignancies. Pts. received subcutaneous GM-CSF at 500 mcg/day on days 1–14 and IL-2 at 1 × 106 units/m2/day on days 8–14. Pts. were off immunosuppressive therapy and had no prior history of graft versus host disease (GVHD) at the start of treatment. Twelve pts. received IL-2/GM-CSF for treatment of relapse AML (7), ALL (2), CML (1), MDS (2). Median age was 55 (range 8–66). Stem cell sources included: peripheral blood = 9, bone marrow = 2, umbilical cord blood (UCB) = 1. Donor sources were: match-related sibling = 4 and match-unrelated donor = 8 (UCB=1). Nine pts. had resistant relapse or primary resistant disease at time of ASCT. Median time from transplant to relapse was 4 months (range = 1–14). Two pts. had failed DLI and 5 pts. had received reinduction chemotherapy prior to IL-2/GM-CSF. Eight pts. responded to IL-2/GM-CSF (CR = 7, PR = 1). Two pts. remain disease free at 18 and 26 months post IL-2/ GM-CSF. Six pts. developed GVHD and of these 4 were responders. Two pts. had GM-CSF discontinued due to increase in peripheral blood blasts. No other toxicities related to IL-2/GM-CSF except for mild flu-like symptoms. The table below summarizes quantitative analysis of immune activation. Values represent means +/− standard error at day 0 (first day of GM-CSF), day 8 (prior to start of IL-2) and day 14 (last day of IL-2 and GM-CSF). P-values are based on paired t-test analysis of day 8 versus day 0 and day 14 versus day 0, respectively. Flow cytometric analysis showed an increase in the numbers of T-lymphocytes (CD3) and T-cell subsets (CD3/CD8 and CD3/CD4) as well as an increase in natural killer cells (CD16/56). Although no differences were seen in the number of dendritic cell subsets, DC1/DC2 ratios decreased with the administration of GM-CSF/IL-2. Limited (n= 4) CD4/FoxP3 analysis did not show change in absolute numbers with administration of GM-CSF/IL-2 (data not shown). In conclusion, cytokine therapy with IL-2/GM-CSF is well tolerated and is an alternative to DLI for relapse after ASCT. Flow cytometry analysis demonstrated a quantitative increase in immune effector cells and polarization to DC2. IMMUNE ACTIVATION FLOW CYTOMETRY ASSAYS D0 (Mean +/− SE) D8 (Mean +/− SE) D14 (Mean +/− SE) P-Value (Day7–0) P-Value (Day 14–0) SE=Standard Error; DC = dendritic cells CD3 (K/uL) 309 +/− 117 535 +/− 103 1306 +/− 403 0.034 0.027 CD3/CD8 (K/uL) 94 +/− 42 174 +/− 33 325 +/− 90 0.021 0.029 CD3/CD4 (K/uL) 309 +/− 117 404 +/− 102 977 +/− 310 0.249 0.045 CD16/CD56 (K/uL) 124 +/− 60 404 +/− 110 496 +/− 162 0.029 0.044 CD19 K/uL) 68 +/−39 89 +/− 36 116 +/− 31 0.183 0.044 Total Lymphs (K/uL 488 +/− 167 942 +/− 160 2353 +/− 532 0.016 0.013 CD11(DC1) (K/uL) 97.1 +/− 60.7 46.3 +/− 32.5 32.6 +/− 27.5 0.108 0.101 CD123(DC2) (K/uL) 32.1 +/− 7.3 39.7 +/− 15.9 45.4 +/− 35.8 0.694 0.628 DC1/DC2 2.77 +/− 1.26 0.68 +/− 0.35 0.61 +/− 0.07

scholarly journals Granulocyte-macrophage colony-stimulating factor neuroprotective activities in Alzheimer’s disease mice

2018 ◽  
Vol 319 ◽  
pp. 80-92 ◽  
Author(s):  
Tomomi Kiyota ◽  
Jatin Machhi ◽  
Yaman Lu ◽  
Bhagyalaxmi Dyavarshetty ◽  
Maryam Nemati ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Colony Stimulating Factor ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor
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