P3-390: The synthetic retinoid, AHPN, attenuates lipopolysaccharide and β-amyloid-induced microglial activation: A possible therapeutic agent for inflammatory-mediated neurodegenerative diseases

Modulation of the innate immune system is emerging as a promising therapeutic strategy against Alzheimer's disease (AD). However, determinants of a beneficial therapeutic effect are ill-understood. Thus, we investigated the potential of 18 kDa translocator protein positron-emission-tomography (TSPO-PET) for assessment of microglial activation in mouse brain before and during chronic immunomodulation. Serial TSPO-PET was performed during five months of chronic microglia modulation by stimulation of peroxisome proliferator-activated receptor (PPAR)-γ with pioglitazone in two different mouse models of AD (PS2APP, AppNL-G-F). Using mixed statistical models on longitudinal TSPO-PET data, we tested for effects of therapy and sex on treatment response. We tested correlations of baseline with longitudinal measures of TSPO-PET, and correlations between PET results with spatial learning performance and β-amyloid accumulation of individual mice. Immunohistochemistry was used to determine the molecular source of the TSPO-PET signal. Pioglitazone-treated female PS2APP and AppNL-G-F mice showed attenuation of the longitudinal increases in TSPO-PET signal when compared to vehicle controls, whereas treated male AppNL-G-F mice showed the opposite effect. Baseline TSPO-PET strongly predicted changes in microglial activation in treated mice (R=-0.874, p<0.0001) but not in vehicle controls (R=-0.356, p=0.081). Reduced TSPO-PET signal upon treatment was associated with better spatial learning and higher fibrillar β-amyloid accumulation. Immunohistochemistry confirmed activated microglia to be the source of the TSPO-PET signal (R=0.952, p<0.0001). TSPO-PET represents a sensitive biomarker for monitoring of immunomodulation and closely reflects activated microglia. Pre-therapeutic assessment of baseline microglial activation and sex are strong predictors of individual immunomodulation effects and could serve for responder stratification.

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Cellular demise and inflammatory microglial activation during β-amyloid toxicity are governed by Wnt1 and canonical signaling pathways

Cellular Signalling ◽

10.1016/j.cellsig.2006.12.009 ◽

2007 ◽

Vol 19 (6) ◽

pp. 1150-1162 ◽

Cited By ~ 49

Author(s):

Zhao Zhong Chong ◽

Faqi Li ◽

Kenneth Maiese

Keyword(s):

Signaling Pathways ◽

Microglial Activation ◽

Amyloid Toxicity ◽

Β Amyloid

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Neuroinflammation, microglial activation, and glucose metabolism in neurodegenerative diseases

International Review of Neurobiology - Metabolic and Bioenergetic Drivers of Neurodegenerative Disease: Neurodegenerative Disease Research and Commonalities with Metabolic Diseases ◽

10.1016/bs.irn.2020.03.017 ◽

2020 ◽

pp. 325-344

Author(s):

Paul Edison

Keyword(s):

Glucose Metabolism ◽

Neurodegenerative Diseases ◽

Microglial Activation

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S3-02-04: MICROGLIAL ACTIVATION IN NEURODEGENERATIVE DISEASES: OPPORTUNITIES FOR THERAPEUTIC INTERVENTION

Alzheimer s & Dementia ◽

10.1016/j.jalz.2018.06.2738 ◽

2006 ◽

Vol 14 (7S_Part_18) ◽

pp. P995-P995

Author(s):

Diego Gomez-Nicola

Keyword(s):

Neurodegenerative Diseases ◽

Therapeutic Intervention ◽

Microglial Activation

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G-CSF rescues the memory impairment of animal models of Alzheimer's disease

Journal of Experimental Medicine ◽

10.1084/jem.20062481 ◽

2007 ◽

Vol 204 (6) ◽

pp. 1273-1280 ◽

Cited By ~ 86

Author(s):

Kuen-Jer Tsai ◽

Yueh-Chiao Tsai ◽

Che-Kun James Shen

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Memory Impairment ◽

Therapeutic Agent ◽

Subcutaneous Administration ◽

Hematopoietic Stem ◽

Amyloid Aβ ◽

Β Amyloid ◽

Stimulating Factor ◽

Tg2576 Mice

Most of the current clinical treatments for Alzheimer's disease (AD) are largely symptomatic and can have serious side effects. We have tested the feasibility of using the granulocyte colony-stimulating factor (G-CSF), which is known to mobilize hematopoietic stem cells (HSCs) from the bone marrow into the peripheral blood, as a therapeutic agent for AD. Subcutaneous administration of G-CSF into two different β-amyloid (Aβ)–induced AD mouse models substantially rescued their cognitive/memory functions. The rescue was accompanied by the accumulation of 5-bromo-2′deoxyuridine–positive HSCs, as well as local neurogenesis surrounding the Aβ aggregates. Furthermore, the level of acetylcholine in the brains of Tg2576 mice was considerably enhanced upon G-CSF treatment. We suggest that G-CSF, a drug already extensively used for treating chemotherapy-induced neutropenia, should be pursued as a novel, noninvasive therapeutic agent for the treatment of AD.

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SOCS1 Mediates Berberine-Induced Amelioration of Microglial Activated States in N9 Microglia Exposed to β Amyloid

BioMed Research International ◽

10.1155/2021/9311855 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Qi Guo ◽

Chen Wang ◽

Xiaorong Xue ◽

Bin Hu ◽

He Bao

Keyword(s):

Neurotrophic Factor ◽

Microglial Activation ◽

Microglial Cells ◽

Enzyme Linked Immunosorbent Assay ◽

Cytokine Signaling ◽

Arginase 1 ◽

Inos Protein Expression ◽

Activated State ◽

Β Amyloid ◽

Factor Α

Attenuating β amyloid- (Aβ-) induced microglial activation is considered to be effective in treating Alzheimer’s disease (AD). Berberine (BBR) can reduce microglial activation in Aβ-treated microglial cells; the mechanism, however, is still illusive. Silencing of cytokine signaling factor 1 (SOCS1) is the primary regulator of many cytokines involved in immune reactions, whose upregulation can reverse the activation of microglial cells. Microglia could be activated into two different statuses, classic activated state (M1 state) and alternative activated state (M2 state), and M1 state is harmful, but M2 is beneficial. In the present study, N9 microglial cells were exposed to Aβ to imitate microglial activation in AD. And Western blot and immunocytochemistry were taken to observe inducible nitric oxide synthase (iNOS), Arginase-1 (Arg-1), and SOCS1 expressions, and the enzyme-linked immunosorbent assay (ELISA) was used to measure inflammatory and neurotrophic factor release. Compared with the normal cultured control cells, Aβ exposure markedly increased the level of microglial M1 state markers ( P < 0.05 ), including iNOS protein expression, tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and IL-6 releases, and BBR administration upregulated SOSC1 expression and the level of microglial M2 state markers ( P < 0.05 ), such as Arg-1 expression, brain-derived neurotrophic factor (BDNF), and glial cell-derived neurotrophic factor (GDNF) releases, downregulating the SOCS1 expression by using siRNA, however, significantly reversed the BBR-induced effects on microglial M1 and M2 state markers and SOCS1 expression ( P < 0.05 ). These findings indicated that BBR can inhibit Aβ-induced microglial activation via modulating the microglial M1/M2 activated state, and SOCS1 mediates the process.

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Fluid Biomarkers Indicative of Neurodegenerative Diseases

10.1093/med/9780190233563.003.0008 ◽

2016 ◽

Author(s):

Henrik Zetterberg ◽

Jonathan M. Schott

Keyword(s):

Central Nervous System ◽

Neurodegenerative Diseases ◽

Microglial Activation ◽

Psychiatric Symptoms ◽

Neuronal Loss ◽

Protein Accumulation ◽

Time Line ◽

The Past ◽

Neurodegenerative Process ◽

Disease Specific

A major unifying feature of neurodegenerative diseases (NDDs) is excessive neuronal loss. Depending on when and where this occurs, patients may express distinct neurological and psychiatric symptoms. Neurodegeneration is accompanied by protein aggregation, inflammation, and microglial activation that may be drivers of the disease or in some circumstances may be protective reactions to the neurodegenerative process. A key development over the past decade has been our ability to leverage these accompanying central nervous system changes to develop clinically impactful biomarkers of specific NDDs. This has been crucial in helping us develop an understanding the time line of progression of these diseases, in their early diagnosis and to help target patients appropriately in therapeutic clinical trials, This chapter gives an overview of both established and novel fluid biomarkers for neurodegeneration, protein accumulation, inflammation, and microglial activation across different neurodegenerative diseases. Common as well as disease-specific biomarker changes in cerebrospinal fluid and blood are emphasized.

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Transmissible Endosomal Intoxication: A Balance between Exosomes and Lysosomes at the Basis of Intercellular Amyloid Propagation

Biomedicines ◽

10.3390/biomedicines8080272 ◽

2020 ◽

Vol 8 (8) ◽

pp. 272

Author(s):

Anaïs Bécot ◽

Charlotte Volgers ◽

Guillaume van Niel

Keyword(s):

Amyloid Precursor Protein ◽

Neurodegenerative Diseases ◽

Multivesicular Body ◽

Precursor Protein ◽

Aβ Peptides ◽

Amyloid Aβ ◽

Β Amyloid ◽

Novel Concept ◽

The Brain

In Alzheimer′s disease (AD), endolysosomal dysfunctions are amongst the earliest cellular features to appear. Each organelle of the endolysosomal system, from the multivesicular body (MVB) to the lysosome, contributes to the homeostasis of amyloid precursor protein (APP) cleavage products including β-amyloid (Aβ) peptides. Hence, this review will attempt to disentangle how changes in the endolysosomal system cumulate to the generation of toxic amyloid species and hamper their degradation. We highlight that the formation of MVBs and the generation of amyloid species are closely linked and describe how the molecular machineries acting at MVBs determine the generation and sorting of APP cleavage products towards their degradation or release in association with exosomes. In particular, we will focus on AD-related distortions of the endolysomal system that divert it from its degradative function to favour the release of exosomes and associated amyloid species. We propose here that such an imbalance transposed at the brain scale poses a novel concept of transmissible endosomal intoxication (TEI). This TEI would initiate a self-perpetuating transmission of endosomal dysfunction between cells that would support the propagation of amyloid species in neurodegenerative diseases.

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