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.

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 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.

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 Association of CSF Proteins With Tau and Amyloid β Levels in Asymptomatic 70-year-olds 

2020 ◽  
Author(s):  
Julia Remnestål ◽  
Sofia Bergström ◽  
Jennie Olofsson ◽  
Evelina Sjöstedt ◽  
Mathias Uhlén ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Csf Biomarkers ◽  
Tau Pathology ◽  
Clinical Dementia Rating ◽  
Disease Biomarkers ◽  
Protein Levels ◽  
Total Tau ◽  
Csf Proteins ◽  
Csf Levels

Abstract BackgroundIncreased knowledge of the evolution of molecular changes in neurodegenerative disorders such as Alzheimer’s disease (AD) is important for the understanding of disease pathophysiology and also crucial to be able to identify and validate disease biomarkers. While several biological changes that occur early in the disease development have already been recognised, the need for further characterization of the pathophysiological mechanisms behind AD still remains.MethodsIn this study, we investigated cerebrospinal fluid (CSF) levels of 104 proteins in 307 asymptomatic 70-year-olds from the H70 Gothenburg Birth Cohort Studies using a multiplexed antibody-based technology. ResultsThe protein levels were first correlated with the core AD CSF biomarker concentrations of total tau, phospho-tau and Aβ42 in all individuals. Sixty-three proteins showed significant correlations with either total tau, phospho-tau or Aβ42. Thereafter, individuals were divided based on CSF Aβ42/Aβ40 ratio and Clinical Dementia Rating (CDR) score to determine if early changes in pathology and cognition had an effect on the correlations. We compared the associations of the analysed proteins to CSF markers between groups and found 33 proteins displaying significantly different associations for amyloid-positive individuals and amyloid negative individuals, as defined by the CSF Aβ42/Aβ40 ratio. No differences in the associations could be seen for individuals divided by CDR score.ConclusionsWe identified a series of transmembrane proteins, proteins associated to or anchored to the plasma membrane, and proteins involved in or connected to synaptic vesicle transport that were associated with CSF biomarkers of amyloid and tau pathology in AD. Further studies are needed to explore their role in AD pathophysiology.

scholarly journals Association of CSF proteins with tau and amyloid β levels in asymptomatic 70-year-olds

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Julia Remnestål ◽  
Sofia Bergström ◽  
Jennie Olofsson ◽  
Evelina Sjöstedt ◽  
Mathias Uhlén ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Csf Biomarkers ◽  
Tau Pathology ◽  
Clinical Dementia Rating ◽  
Disease Biomarkers ◽  
Protein Levels ◽  
Total Tau ◽  
Csf Proteins ◽  
Csf Levels

Abstract Background Increased knowledge of the evolution of molecular changes in neurodegenerative disorders such as Alzheimer’s disease (AD) is important for the understanding of disease pathophysiology and also crucial to be able to identify and validate disease biomarkers. While several biological changes that occur early in the disease development have already been recognized, the need for further characterization of the pathophysiological mechanisms behind AD still remains. Methods In this study, we investigated cerebrospinal fluid (CSF) levels of 104 proteins in 307 asymptomatic 70-year-olds from the H70 Gothenburg Birth Cohort Studies using a multiplexed antibody- and bead-based technology. Results The protein levels were first correlated with the core AD CSF biomarker concentrations of total tau, phospho-tau and amyloid beta (Aβ42) in all individuals. Sixty-three proteins showed significant correlations to either total tau, phospho-tau or Aβ42. Thereafter, individuals were divided based on CSF Aβ42/Aβ40 ratio and Clinical Dementia Rating (CDR) score to determine if early changes in pathology and cognition had an effect on the correlations. We compared the associations of the analysed proteins with CSF markers between groups and found 33 proteins displaying significantly different associations for amyloid-positive individuals and amyloid-negative individuals, as defined by the CSF Aβ42/Aβ40 ratio. No differences in the associations could be seen for individuals divided by CDR score. Conclusions We identified a series of transmembrane proteins, proteins associated with or anchored to the plasma membrane, and proteins involved in or connected to synaptic vesicle transport to be associated with CSF biomarkers of amyloid and tau pathology in AD. Further studies are needed to explore these proteins’ role in AD pathophysiology.

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 Association of CSF proteins with tau and amyloid β levels in asymptomatic 70-year-olds

2021 ◽  
Author(s):  
Julia Remnestål ◽  
Sofia Bergström ◽  
Jennie Olofsson ◽  
Evelina Sjöstedt ◽  
Mathias Uhlén ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Csf Biomarkers ◽  
Tau Pathology ◽  
Clinical Dementia Rating ◽  
Disease Biomarkers ◽  
Protein Levels ◽  
Total Tau ◽  
Csf Proteins ◽  
Csf Levels

Abstract BackgroundIncreased knowledge of the evolution of molecular changes in neurodegenerative disorders such as Alzheimer’s disease (AD) is important for the understanding of disease pathophysiology and also crucial to be able to identify and validate disease biomarkers. While several biological changes that occur early in the disease development have already been recognised, the need for further characterization of the pathophysiological mechanisms behind AD still remains.MethodsIn this study, we investigated cerebrospinal fluid (CSF) levels of 104 proteins in 307 asymptomatic 70-year-olds from the H70 Gothenburg Birth Cohort Studies using a multiplexed antibody- and bead-based technology. ResultsThe protein levels were first correlated with the core AD CSF biomarker concentrations of total tau, phospho-tau and amyloid beta (Aβ42) in all individuals. Sixty-three proteins showed significant correlations to either total tau, phospho-tau or Aβ42. Thereafter, individuals were divided based on CSF Aβ42/Aβ40 ratio and Clinical Dementia Rating (CDR) score to determine if early changes in pathology and cognition had an effect on the correlations. We compared the associations of the analysed proteins with CSF markers between groups and found 33 proteins displaying significantly different associations for amyloid-positive individuals and amyloid-negative individuals, as defined by the CSF Aβ42/Aβ40 ratio. No differences in the associations could be seen for individuals divided by CDR score.ConclusionsWe identified a series of transmembrane proteins, proteins associated with or anchored to the plasma membrane, and proteins involved in or connected to synaptic vesicle transport to be associated with CSF biomarkers of amyloid and tau pathology in AD. Further studies are needed to explore these proteins’ role in AD pathophysiology.

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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