scholarly journals Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways

2021 ◽  
Author(s):  
Kristen Ibanez ◽  
Karen McFarland ◽  
Jennifer Phillips ◽  
Mariet Allen ◽  
Christian B Lessard ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Microglial Cells ◽  
Rodent Models ◽  
Rna Seq ◽  
Tau Pathology ◽  
Gene Dose ◽  
Age Dependent ◽  
Glial Function ◽  
Opposing Effects

The S209F variant of Abelson Interactor Protein 3 (ABI3) increases risk for Alzheimer's disease (AD), but little is known about ABI3 function. RNAscope showed Abi3 is expressed in microglial and non-microglial cells, though its increased expression appears to be driven in plaque-associated microglia. Here, we evaluated Abi3-/- mice and document that both Abi3 and its overlapping gene, Gngt2, are disrupted in these mice. Expression of Abi3 and Gngt2 are tightly correlated, and elevated, in rodent models of AD. RNA-seq of the Abi3-Gngt2-/- mice revealed robust induction of an AD-associated neurodegenerative signature, including upregulation of Trem2, Plcg2 and Tyrobp. In APP mice, loss of Abi3-Gngt2 resulted in a gene dose- and age-dependent reduction in A? deposition. Additionally, in Abi3-Gngt2-/- mice, expression of a pro-aggregant form of human tau exacerbated tauopathy and astrocytosis. Further, the AD-associated S209F mutation alters the extent of ABI3 phosphorylation. These data provide an important experimental framework for understanding the role of Abi3-Gngt2 function in AD. Our studies also demonstrate that manipulation of glial function could have opposing effects on amyloid and tau pathology, highlighting the unpredictability of targeting such pathways in AD.

scholarly journals Neuronutraceuticals Modulate Lipopolysaccharide- or Amyloid-β 1-42 Peptide-Induced Transglutaminase 2 Overexpression as a Marker of Neuroinflammation in Mouse Microglial Cells

2021 ◽  
Vol 11 (12) ◽  
pp. 5718
Author(s):  
Nicola Gaetano Gatta ◽  
Andrea Parente ◽  
Francesca Guida ◽  
Sabatino Maione ◽  
Vittorio Gentile
Keyword(s):  
Microglial Cell ◽  
Amyloid Β ◽  
Transglutaminase 2 ◽  
Microglial Cells ◽  
Tissue Type ◽  
Microglial Cell Line ◽  
Bv2 Cells ◽  
Important Marker

Background: Tissue type 2 transglutaminase (TG2, E.C. 2.3.2,13) is reported to be involved in the phagocytosis of apoptotic cells in mouse microglial BV2 cells and peripheral macrophages. In this study, by using lipopolysaccharide (LPS)- or amyloid-β 1-42 (Aβ 1-42) peptide-stimulated microglial cell line BV2 and mouse primary microglial cells, we examined the effects of different neuronutraceutical compounds, such as curcumin (Cu) and N-Palmitoylethanolamine (PEA), known for their anti-inflammatory activity, on TG2 and several inflammatory or neuroprotective biomarker expressions. Methods: Mouse BV2 cells were treated with LPS or Aβ1-42 in the presence of curcumin or PEA, in order to evaluate the expression of TG2 and other inflammatory or neuroprotective markers using Real Time-PCR and Western blot analyses. Results: Curcumin and PEA were capable of reducing TG2 expression in mouse microglial cells during co-treatment with LPS or Aβ 1-42. Conclusions: The results show the role of TG2 as an important marker of neuroinflammation and suggest a possible use of curcumin and PEA in order to reduce LPS- or Aβ1-42-induced TG2 overexpression in mouse microglial cells.

scholarly journals Astrocytes and neuroinflammation in Alzheimer's disease

2014 ◽  
Vol 42 (5) ◽  
pp. 1321-1325 ◽  
Author(s):  
Emma C. Phillips ◽  
Cara L. Croft ◽  
Ksenia Kurbatskaya ◽  
Michael J. O’Neill ◽  
Michael L. Hutton ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Inflammatory Responses ◽  
Amyloid Β ◽  
Synaptic Dysfunction ◽  
Amyloid Β Peptide ◽  
Substantial Evidence ◽  
Models Of Disease ◽  
Opposing Effects

Increased production of amyloid β-peptide (Aβ) and altered processing of tau in Alzheimer's disease (AD) are associated with synaptic dysfunction, neuronal death and cognitive and behavioural deficits. Neuroinflammation is also a prominent feature of AD brain and considerable evidence indicates that inflammatory events play a significant role in modulating the progression of AD. The role of microglia in AD inflammation has long been acknowledged. Substantial evidence now demonstrates that astrocyte-mediated inflammatory responses also influence pathology development, synapse health and neurodegeneration in AD. Several anti-inflammatory therapies targeting astrocytes show significant benefit in models of disease, particularly with respect to tau-associated neurodegeneration. However, the effectiveness of these approaches is complex, since modulating inflammatory pathways often has opposing effects on the development of tau and amyloid pathology, and is dependent on the precise phenotype and activities of astrocytes in different cellular environments. An increased understanding of interactions between astrocytes and neurons under different conditions is required for the development of safe and effective astrocyte-based therapies for AD and related neurodegenerative diseases.

scholarly journals Integrative brain transcriptome analysis links complement component 4 and HSPA2 to the APOE ε2 protective effect in Alzheimer disease

2021 ◽  
Author(s):  
Rebecca Panitch ◽  
Junming Hu ◽  
Jaeyoon Chung ◽  
Congcong Zhu ◽  
Gaoyuan Meng ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Protective Effect ◽  
Amyloid Β ◽  
Oligodendrocyte Progenitor Cells ◽  
Expression Data ◽  
Complement Pathway ◽  
Tau Pathology ◽  
Brain Transcriptome ◽  
Complement Component 4

AbstractMechanisms underlying the protective effect of apolipoprotein E (APOE) ε2 against Alzheimer disease (AD) are not well understood. We analyzed gene expression data derived from autopsied brains donated by 982 individuals including 135 APOE ɛ2/ɛ3 carriers. Complement pathway genes C4A and C4B were among the most significantly differentially expressed genes between ɛ2/ɛ3 AD cases and controls. We also identified an APOE ε2/ε3 AD-specific co-expression network enriched for astrocytes, oligodendrocytes and oligodendrocyte progenitor cells containing the genes C4A, C4B, and HSPA2. These genes were significantly associated with the ratio of phosphorylated tau at position 231 to total Tau but not with amyloid-β 42 level, suggesting this APOE ɛ2 related co-expression network may primarily be involved with tau pathology. HSPA2 expression was oligodendrocyte-specific and significantly associated with C4B protein. Our findings provide the first evidence of a crucial role of the complement pathway in the protective effect of APOE ε2 for AD.

scholarly journals Determining the role of IL-4 induced neuroinflammation in microglial activity and amyloid-β using BV2 microglial cells and APP/PS1 transgenic mice

2015 ◽  
Vol 12 (1) ◽  
pp. 41 ◽  
Author(s):  
Clare H Latta ◽  
Tiffany L Sudduth ◽  
Erica M Weekman ◽  
Holly M Brothers ◽  
Erin L Abner ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Amyloid Β ◽  
Microglial Cells ◽  
Bv2 Microglial Cells

scholarly journals Integrative Brain Transcriptome Analysis Links Complement Component 4 and HSPA2 to the APOE ε2 Protective Effect in Alzheimer Disease

2020 ◽  
Author(s):  
Rebecca Panitch ◽  
Junming Hu ◽  
Jaeyoon Chung ◽  
Congcong Zhu ◽  
Gaoyuan Meng ◽  
...  
Keyword(s):  
Protective Effect ◽  
Amyloid Β ◽  
Oligodendrocyte Progenitor Cells ◽  
Expression Data ◽  
Complement Pathway ◽  
Tau Pathology ◽  
Total Tau ◽  
Brain Transcriptome ◽  
Complement Component 4

AbstractMechanisms underlying the protective effect of apolipoprotein E (APOE) ε2 against Alzheimer’s disease (AD) are not well understood. We analyzed gene expression data derived from autopsied brains donated by 982 individuals including 135 APOE ε 2/ε 3 carriers. Complement pathway genes C4A and C4B were among the most significantly differentially expressed genes between ε 2/ε 3 AD cases and controls. We also identified an APOE ε2/ε3 AD-specific co-expression network enriched for astrocytes, oligodendrocytes and oligodendrocyte progenitor cells containing the genes C4A, C4B, and HSPA2. These genes were significantly associated with the ratio of phosphorylated tau at position 231 to total Tau but not with amyloid-β 42 level, suggesting this APOE ε 2 related co-expression network may primarily be involved with tau pathology. HSPA2 expression was oligodendrocyte specific and significantly associated with C4B protein. Our findings provide the first evidence of a crucial role of the complement pathway in the protective effect of APOE ε2 for AD.

Neuroinflammation in Alzheimer’s disease: focus on NLRP1 and NLRP3 inflammasomes

2021 ◽  
Vol 22 ◽  
Author(s):  
Eliana Cristina de Brito Toscano ◽  
Natalia Pessoa Rocha ◽  
Beatriz Noele Azevedo Lopes ◽  
Claudia Kimie Suemoto ◽  
Antonio Lucio Teixeira
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Experimental Models ◽  
Tau Pathology ◽  
Relevant Role ◽  
Nlrp3 Inflammasomes ◽  
Amyloid Cascade ◽  
Disease Focus

Background: Alzheimer’s disease (AD) is the main cause of dementia worldwide. The definitive diagnosis of AD is clinicopathological and based on the identification of cerebral deposition of amyloid β (Aβ) plaques and neurofibrillary tangles. However, the link between amyloid cascade and depositions of phosphorylated tau (p-tau) is still missing. In this scenario, inflammasomes might play a relevant role. Experimental models of AD have suggested that Aβ accumulation induces, through microglia, activation of the NLRP3 inflammasome. This activation contributes to the dissemination of Aβ and p-tau, as well as to hyperphosphorylation of tau. Also in experimental models, NLPR1 promoted neuronal pyroptosis. There are neither comprehensive neuropathologic characterization, nor clinicopathologic studies evaluating the NLRP1 and NLRP3 inflammasomes in subjects with AD. Objective: The current mini-review aims to summarize recent and promising findings on the role of NLRP1 and NLRP3 signaling in the pathophysiology of AD. We also sought to highlight the knowledge gap in patients with AD, mainly the lack of clinicopathologic studies on the interaction among inflammasomes, Aβ/tau pathology, and cognitive decline.

scholarly journals Relative Contribution of Amyloid-β Plaque Associated And Plaque Distant Microglia To Alzheimer’s Disease (AD) Progression

2021 ◽  
Author(s):  
Anne-Laure Hemonnot-Girard ◽  
Cédric Meersseman ◽  
Manuela Pastore ◽  
Nathalie Linck ◽  
Catherine Rey ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Spatial Information ◽  
Amyloid Β ◽  
Functional Roles ◽  
Relative Contribution ◽  
Negative Impacts ◽  
Opposing Effects ◽  
Transcriptomic Changes

Abstract Background: Research in recent years firmly established that microglial cells play an important role in the pathogenesis of Alzheimer's disease (AD). In parallel, a series of studies showed that, under both homeostatic and pathological conditions, microglia are a heterogeneous cell population. In AD, amyloid-b (Ab) plaque-associated microglia (PAM) display a clearly distinct phenotype compared to plaque-distant microglia (PCM), suggesting that these two microglia subtypes likely differently contribute to disease progression. Methods: In this study, we combined cell-specific laser capture and RNA-seq analysis to investigate the functional role of both plaque-associated and plaque-distant microglia. Results: First, we established that this approach allows selective isolation of microglia, while preserving spatial information and preventing transcriptome changes induced by classical purification approaches. Then, we identified, in both microglia subpopulations, networks of co-deregulated genes and analyzed their potential functional roles in AD. In addition, we investigated the dynamics of microglia transcriptomic remodeling at early, intermediate and late stages of the disease. Conclusions: Our comprehensive study demonstrates that the proximity of microglia to Ab-plaques dramatically alters the microglial transcriptome and reveals that these changes can have both positive and negative impacts on the surrounding cells. These opposing effects may be driven by local microglia heterogeneity also demonstrated by this study. Our results also suggest that Ab plaque-associated microglia undergo exhaustion in the later stage of the disease. Our approach also allowed to molecularly define the overlooked plaque-distant microglia. We show, that although the transcriptomic changes are far less striking compared to what is observed in plaque-associated microglia, plaque-distant microglia are not bystanders of the disease. In particular, our results suggest they are involved in Ab oligomer detection and in Ab-plaque initiation, with increased contribution as the disease progresses.

scholarly journals The Role of Protein Misfolding and Tau Oligomers (TauOs) in Alzheimer′s Disease (AD)

2019 ◽  
Vol 20 (19) ◽  
pp. 4661 ◽  
Author(s):  
Mroczko ◽  
Groblewska ◽  
Litman-Zawadzka
Keyword(s):  
Protein Misfolding ◽  
Mini Mental State Examination ◽  
Amyloid Β ◽  
Csf Biomarkers ◽  
Causative Role ◽  
Tau Pathology ◽  
Tau Oligomers ◽  
Pubmed Database ◽  
State Examination

Although the causative role of the accumulation of amyloid β 1–42 (Aβ42) deposits in the pathogenesis of Alzheimer′s disease (AD) has been under debate for many years, it is supposed that the toxicity soluble oligomers of Tau protein (TauOs) might be also the pathogenic factor acting on the initial stages of this disease. Therefore, we performed a thorough search for literature pertaining to our investigation via the MEDLINE/PubMed database. It was shown that soluble TauOs, especially granular forms, may be the most toxic form of this protein. Hyperphosphorylated TauOs can reduce the number of synapses by missorting into axonal compartments of neurons other than axon. Furthermore, soluble TauOs may be also responsible for seeding Tau pathology within AD brains, with probable link to AβOs toxicity. Additionally, the concentrations of TauOs in the cerebrospinal fluid (CSF) and plasma of AD patients were higher than in non-demented controls, and revealed a negative correlation with mini-mental state examination (MMSE) scores. It was postulated that adding the measurements of TauOs to the panel of CSF biomarkers could improve the diagnosis of AD.

scholarly journals The Role of Eicosanoids in Alzheimer’s Disease

2019 ◽  
Vol 16 (14) ◽  
pp. 2560 ◽  
Author(s):  
Roger G. Biringer
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Biological Functions ◽  
Tau Pathology ◽  
Cellular Processes ◽  
Eicosanoid Metabolism ◽  
Underlying Mechanisms

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders known. Estimates from the Alzheimer’s Association suggest that there are currently 5.8 million Americans living with the disease and that this will rise to 14 million by 2050. Research over the decades has revealed that AD pathology is complex and involves a number of cellular processes. In addition to the well-studied amyloid-β and tau pathology, oxidative damage to lipids and inflammation are also intimately involved. One aspect all these processes share is eicosanoid signaling. Eicosanoids are derived from polyunsaturated fatty acids by enzymatic or non-enzymatic means and serve as short-lived autocrine or paracrine agents. Some of these eicosanoids serve to exacerbate AD pathology while others serve to remediate AD pathology. A thorough understanding of eicosanoid signaling is paramount for understanding the underlying mechanisms and developing potential treatments for AD. In this review, eicosanoid metabolism is examined in terms of in vivo production, sites of production, receptor signaling, non-AD biological functions, and known participation in AD pathology.

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