scholarly journals Differences in Immune-Related Genes Underlie Temporal and Regional Pathological Progression in 3xTg-AD Mice

Cells ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 137
Author(s):  
Adelaide Fernandes ◽  
Cláudia Caldeira ◽  
Carolina Cunha ◽  
Elisabete Ferreiro ◽  
Ana Rita Vaz ◽  
...  
Keyword(s):  
Target Genes ◽  
Amyloid Β ◽  
Brain Regions ◽  
Risk Genes ◽  
App Processing ◽  
Mhc Ii ◽  
Arginase 1 ◽  
Tnf Α ◽  
Immune Related Genes ◽  
The Brain

The prevalence of Alzheimer’s disease (AD), the most common cause of age-associated dementia, is estimated to increase over the next decades. Evidence suggests neuro-immune signaling deregulation and risk genes beyond the amyloid-β (Aβ) deposition in AD pathology. We examined the temporal profile of inflammatory mediators and microglia deactivation/activation in the brain cortex and hippocampus of 3xTg-AD mice at 3- and 9-month-old. We found upregulated APP processing, decreased expression of CD11b, CX3CR1, MFG-E8, TNF-α, IL-1β, MHC-II and C/EBP-α and increased miR-146a in both brain regions in 3-month-old 3xTG-AD mice, suggestive of a restrictive regulation. Enhanced TNF-α, IL-1β, IL-6, iNOS, SOCS1 and Arginase 1 were only present in the hippocampus of 9-month-old animals, though elevation of HMGB1 and reduction of miR-146a and miR-124 were common features in the hippocampus and cortex regions. miR-155 increased early in the cortex and later in both regions, supporting its potential as a biomarker. Candidate downregulated target genes by cortical miR-155 included Foxo3, Runx2 and CEBPβ at 3 months and Foxo3, Runx2 and Socs1 at 9 months, which are implicated in cell survival, but also in Aβ pathology and microglia/astrocyte dysfunction. Data provide new insights across AD state trajectory, with divergent microglia phenotypes and inflammatory-associated features, and identify critical targets for drug discovery and combinatorial therapies.

scholarly journals Neuroinflammation and protein pathology in Parkinson’s disease dementia

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Antonina Kouli ◽  
Marta Camacho ◽  
Kieren Allinson ◽  
Caroline H. Williams-Gray
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
T Lymphocytes ◽  
Substantia Nigra ◽  
Amyloid Β ◽  
Brain Regions ◽  
Parkinson’S Disease Dementia ◽  
Activated Microglia ◽  
Cell Counts ◽  
The Brain

AbstractParkinson’s disease dementia is neuropathologically characterized by aggregates of α-synuclein (Lewy bodies) in limbic and neocortical areas of the brain with additional involvement of Alzheimer’s disease-type pathology. Whilst immune activation is well-described in Parkinson’s disease (PD), how it links to protein aggregation and its role in PD dementia has not been explored. We hypothesized that neuroinflammatory processes are a critical contributor to the pathology of PDD. To address this hypothesis, we examined 7 brain regions at postmortem from 17 PD patients with no dementia (PDND), 11 patients with PD dementia (PDD), and 14 age and sex-matched neurologically healthy controls. Digital quantification after immunohistochemical staining showed a significant increase in the severity of α-synuclein pathology in the hippocampus, entorhinal and occipitotemporal cortex of PDD compared to PDND cases. In contrast, there was no difference in either tau or amyloid-β pathology between the groups in any of the examined regions. Importantly, we found an increase in activated microglia in the amygdala of demented PD brains compared to controls which correlated significantly with the extent of α-synuclein pathology in this region. Significant infiltration of CD4+ T lymphocytes into the brain parenchyma was commonly observed in PDND and PDD cases compared to controls, in both the substantia nigra and the amygdala. Amongst PDND/PDD cases, CD4+ T cell counts in the amygdala correlated with activated microglia, α-synuclein and tau pathology. Upregulation of the pro-inflammatory cytokine interleukin 1β was also evident in the substantia nigra as well as the frontal cortex in PDND/PDD versus controls with a concomitant upregulation in Toll-like receptor 4 (TLR4) in these regions, as well as the amygdala. The evidence presented in this study show an increased immune response in limbic and cortical brain regions, including increased microglial activation, infiltration of T lymphocytes, upregulation of pro-inflammatory cytokines and TLR gene expression, which has not been previously reported in the postmortem PDD brain.

scholarly journals Ceramide and Related-Sphingolipid Levels Are Not Altered in Disease-Associated Brain Regions of APPSLand APPSL/PS1M146LMouse Models of Alzheimer's Disease: Relationship with the Lack of Neurodegeneration?

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Laurence Barrier ◽  
Bernard Fauconneau ◽  
Anastasia Noël ◽  
Sabrina Ingrand
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Neuronal Death ◽  
Time Course ◽  
Neuronal Loss ◽  
Brain Regions ◽  
App Processing ◽  
Ceramide Accumulation ◽  
The Brain

There is evidence linking sphingolipid abnormalities, APP processing, and neuronal death in Alzheimer's disease (AD). We previously reported a strong elevation of ceramide levels in the brain of the APPSL/PS1Ki mouse model of AD, preceding the neuronal death. To extend these findings, we analyzed ceramide and related-sphingolipid contents in brain from two other mouse models (i.e., APPSLand APPSL/PS1M146L) in which the time-course of pathology is closer to that seen in most currently available models. Conversely to our previous work, ceramides did not accumulate in disease-associated brain regions (cortex and hippocampus) from both models. However, the APPSL/PS1Ki model is unique for its drastic neuronal loss coinciding with strong accumulation of neurotoxic Aβisoforms, not observed in other animal models of AD. Since there are neither neuronal loss nor toxic Aβspecies accumulation in APPSLmice, we hypothesized that it might explain the lack of ceramide accumulation, at least in this model.

scholarly journals Efficacy and immunogenicity of MultiTEP-based DNA vaccines targeting human α-synuclein: prelude for IND enabling studies

npj Vaccines ◽  
2022 ◽  
Vol 7 (1) ◽  
Author(s):  
Changyoun Kim ◽  
Armine Hovakimyan ◽  
Karen Zagorski ◽  
Tatevik Antonyan ◽  
Irina Petrushina ◽  
...  
Keyword(s):  
Dna Vaccines ◽  
Neurodegenerative Disorder ◽  
Neuronal Damage ◽  
Lewy Bodies ◽  
Amyloid Β ◽  
The Elderly ◽  
Brain Regions ◽  
Dependent Manner ◽  
Lewy Neurites ◽  
The Brain

AbstractAccumulation of misfolded proteins such as amyloid-β (Aβ), tau, and α-synuclein (α-Syn) in the brain leads to synaptic dysfunction, neuronal damage, and the onset of relevant neurodegenerative disorder/s. Dementia with Lewy bodies (DLB) and Parkinson’s disease (PD) are characterized by the aberrant accumulation of α-Syn intracytoplasmic Lewy body inclusions and dystrophic Lewy neurites resulting in neurodegeneration associated with inflammation. Cell to cell propagation of α-Syn aggregates is implicated in the progression of PD/DLB, and high concentrations of anti-α-Syn antibodies could inhibit/reduce the spreading of this pathological molecule in the brain. To ensure sufficient therapeutic concentrations of anti-α-Syn antibodies in the periphery and CNS, we developed four α-Syn DNA vaccines based on the universal MultiTEP platform technology designed especially for the elderly with immunosenescence. Here, we are reporting on the efficacy and immunogenicity of these vaccines targeting three B-cell epitopes of hα-Syn aa85–99 (PV-1947D), aa109–126 (PV-1948D), aa126–140 (PV-1949D) separately or simultaneously (PV-1950D) in a mouse model of synucleinopathies mimicking PD/DLB. All vaccines induced high titers of antibodies specific to hα-Syn that significantly reduced PD/DLB-like pathology in hα-Syn D line mice. The most significant reduction of the total and protein kinase resistant hα-Syn, as well as neurodegeneration, were observed in various brain regions of mice vaccinated with PV-1949D and PV-1950D in a sex-dependent manner. Based on these preclinical data, we selected the PV-1950D vaccine for future IND enabling preclinical studies and clinical development.

scholarly journals Altered Amyloid-β Metabolism and Deposition in Genomic-based β-Secretase Transgenic Mice

2004 ◽  
Vol 279 (50) ◽  
pp. 52535-52542 ◽  
Author(s):  
Matthew J. Chiocco ◽  
Laura Shapiro Kulnane ◽  
Linda Younkin ◽  
Steve Younkin ◽  
Geneviève Evin ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Transgenic Animals ◽  
Brain Regions ◽  
Primary Component ◽  
App Processing ◽  
Bace1 Expression ◽  
First Time

Amyloid-β (Aβ) the primary component of the senile plaques found in Alzheimer's disease (AD) is generated by the rate-limiting cleavage of amyloid precursor protein (APP) by β-secretase followed by γ-secretase cleavage. Identification of the primary β-secretase gene,BACE1, provides a unique opportunity to examine the role this unique aspartyl protease plays in altering Aβ metabolism and deposition that occurs in AD. The current experiments seek to examine how modulating β-secretase expression and activity alters APP processing and Aβ metabolismin vivo. Genomic-basedBACE1transgenic mice were generated that overexpress humanBACE1mRNA and protein. The highest expressingBACE1transgenic line was mated to transgenic mice containing human APP transgenes. Our biochemical and histochemical studies demonstrate that mice overexpressing bothBACE1andAPPshow specific alterations in APP processing and age-dependent Aβ deposition. We observed elevated levels of Aβ isoforms as well as significant increases of Aβ deposits in these double transgenic animals. In particular, the double transgenics exhibited a unique cortical deposition profile, which is consistent with a significant increase of BACE1 expression in the cortex relative to other brain regions. Elevated BACE1 expression coupled with increased deposition provides functional evidence for β-secretase as a primary effector in regional amyloid deposition in the AD brain. Our studies demonstrate, for the first time, that modulation ofBACE1activity may play a significant role in AD pathogenesisin vivo.

scholarly journals Phosphorylation Signaling in APP Processing in Alzheimer’s Disease

2019 ◽  
Vol 21 (1) ◽  
pp. 209 ◽  
Author(s):  
Tao Zhang ◽  
Dongmei Chen ◽  
Tae Ho Lee
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signaling Pathways ◽  
Physiological Function ◽  
Amyloid Β ◽  
Proteolytic Processing ◽  
App Processing ◽  
Abnormal Accumulation ◽  
The Central Nervous System ◽  
The Brain

The abnormal accumulation of amyloid-β (Aβ) in the central nervous system is a hallmark of Alzheimer’s disease (AD). The regulation of the processing of the single- transmembrane amyloid precursor protein (APP) plays an important role in the generation of Aβ in the brain. The phosphorylation of APP and key enzymes involved in the proteolytic processing of APP has been demonstrated to be critical for modulating the generation of Aβ by either altering the subcellular localization of APP or changing the enzymatic activities of the secretases responsible for APP processing. In addition, the phosphorylation may also have an impact on the physiological function of these proteins. In this review, we summarize the kinases and signaling pathways that may participate in regulating the phosphorylation of APP and secretases and how this further affects the function and processing of APP and Aβ pathology. We also discuss the potential of approaches that modulate these phosphorylation-signaling pathways or kinases as interventions for AD pathology.

Understanding the function of ABCA7 in Alzheimer's disease

2015 ◽  
Vol 43 (5) ◽  
pp. 920-923 ◽  
Author(s):  
Hongyun Li ◽  
Tim Karl ◽  
Brett Garner
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Association Studies ◽  
Chinese Hamster Ovary Cells ◽  
Amyloid Β ◽  
Mutant Form ◽  
Genome Wide Association Studies ◽  
App Processing ◽  
The Brain

ATP-binding cassette transporter A7 (ABCA7) is highly expressed in the brain. Recent genome-wide association studies (GWAS) identify ABCA7 single nt polymorphisms (SNPs) that increase Alzheimer's disease (AD) risk. It is now important to understand the true function of ABCA7 in the AD context. We have begun to address this using in vitro and in vivo AD models. Our initial studies showed that transient overexpression of ABCA7 in Chinese hamster ovary cells stably expressing human amyloid precursor protein (APP) resulted in an approximate 50% inhibition in the production of the AD-related amyloid-β (Aβ) peptide as compared with mock-transfected cells. This increased ABCA7 expression was also associated with alterations in other markers of APP processing and an accumulation of cellular APP. To probe for a function of ABCA7 in vivo, we crossed Abca7−/− mice with J20 mice, an amyloidogenic transgenic AD mouse model [B6.Cg-Tg(PDGFB-APPSwInd)20Lms/J] expressing a mutant form of human APP bearing both the Swedish (K670N/M671L) and Indiana (V717F) familial AD mutations. We found that ABCA7 loss doubled insoluble Aβ levels and amyloid plaques in the brain. This did not appear to be related to changes in APP processing (C-terminal fragment analysis), which led us to assess other mechanism by which ABCA7 may modulate Aβ homoeostasis. As we have shown that microglia express high levels of ABCA7, we examined a role for ABCA7 in the phagocytic clearance of Aβ. Our data indicated that the capacity for bone marrow-derived macrophages derived from Abca7−/− mice to phagocytose Aβ was reduced by 51% compared with wild-type (WT) mice. This suggests ABCA7 plays a role in the regulation of Aβ homoeostasis in the brain and that this may be related to Aβ clearance by microglia.

scholarly journals Cell type-specific proteogenomic signal diffusion for integrating multi-omics data predicts novel schizophrenia risk genes

2020 ◽  
Author(s):  
Abolfazl Doostparast Torshizi ◽  
Jubao Duan ◽  
Kai Wang
Keyword(s):  
Single Cell ◽  
Brain Regions ◽  
Cellular Protein ◽  
Cell Protein ◽  
Tissue Cell ◽  
Omics Data ◽  
Cell Type ◽  
Risk Genes ◽  
The Brain ◽  
Polygenic Diseases

AbstractAccumulation of diverse types of omics data on schizophrenia (SCZ) requires a systems approach to jointly modeling the interplay between genome, transcriptome and proteome. Proteome dynamics, as the definitive cellular machinery in human body, has been lagging behind the research on genome/transcriptome in the context of SCZ, both at tissue and single-cell resolution. We introduce a Markov Affinity-based Proteogenomic Signal Diffusion (MAPSD) method to model intra-cellular protein trafficking paradigms and tissue-wise single-cell protein abundances. MAPSD integrates multi-omics data to amplify the signals at SCZ risk loci with small effect sizes, and reveal convergent disease-associated gene modules in the brain interactome as well as more than 130 tissue/cell-type combinations. We predicted a set of high-confidence SCZ risk genes, the majority of which are not directly connected to SCZ susceptibility risk genes. We characterized the subcellular localization of proteins encoded by candidate SCZ risk genes in various brain regions, and illustrated that most are enriched in neuronal and Purkinje cells in cerebral cortex. We demonstrated how the identified gene set may be involved in different developmental stages of the brain, how they alter SCZ-related biological pathways, and how they can be effectively leveraged for drug repurposing. MAPSD can be applied to other polygenic diseases, yet our case study on SCZ signifies how tissue-adjusted protein-protein interaction networks can assist in generating deeper insights into the orchestration of polygenic diseases.

scholarly journals Impact of peripheral myeloid cells on amyloid-β pathology in Alzheimer’s disease–like mice

2015 ◽  
Vol 212 (11) ◽  
pp. 1811-1818 ◽  
Author(s):  
Stefan Prokop ◽  
Kelly R. Miller ◽  
Natalia Drost ◽  
Susann Handrick ◽  
Vidhu Mathur ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Myeloid Cells ◽  
Amyloid Β ◽  
Myeloid Cell ◽  
Amyloid Plaques ◽  
Full Potential ◽  
Antibody Treatment ◽  
App Processing ◽  
The Brain

Although central nervous system–resident microglia are believed to be ineffective at phagocytosing and clearing amyloid-β (Aβ), a major pathological hallmark of Alzheimer’s disease (AD), it has been suggested that peripheral myeloid cells constitute a heterogeneous cell population with greater Aβ-clearing capabilities. Here, we demonstrate that the conditional ablation of resident microglia in CD11b-HSVTK (TK) mice is followed by a rapid repopulation of the brain by peripherally derived myeloid cells. We used this system to directly assess the ability of peripheral macrophages to reduce Aβ plaque pathology and therefore depleted and replaced the pool of resident microglia with peripherally derived myeloid cells in Aβ-carrying APPPS1 mice crossed to TK mice (APPPS1;TK). Despite a nearly complete exchange of resident microglia with peripheral myeloid cells, there was no significant change in Aβ burden or APP processing in APPPS1;TK mice. Importantly, however, newly recruited peripheral myeloid cells failed to cluster around Aβ deposits. Even additional anti-Aβ antibody treatment aimed at engaging myeloid cells with amyloid plaques neither directed peripherally derived myeloid cells to amyloid plaques nor altered Aβ burden. These data demonstrate that mere recruitment of peripheral myeloid cells to the brain is insufficient in substantially clearing Aβ burden and suggest that specific additional triggers appear to be required to exploit the full potential of myeloid cell–based therapies for AD.

scholarly journals Genome-wide coexpression of steroid receptors in the mouse brain: Identifying signaling pathways and functionally coordinated regions

2016 ◽  
Vol 113 (10) ◽  
pp. 2738-2743 ◽  
Author(s):  
Ahmed Mahfouz ◽  
Boudewijn P. F. Lelieveldt ◽  
Aldo Grefhorst ◽  
Lisa T. C. M. van Weert ◽  
Isabel M. Mol ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Mrna Expression ◽  
Mouse Brain ◽  
Estrogen Receptor Alpha ◽  
Target Genes ◽  
Steroid Receptors ◽  
Estrogen Receptor Beta ◽  
Brain Regions ◽  
Genome Wide ◽  
The Brain

Steroid receptors are pleiotropic transcription factors that coordinate adaptation to different physiological states. An important target organ is the brain, but even though their effects are well studied in specific regions, brain-wide steroid receptor targets and mediators remain largely unknown due to the complexity of the brain. Here, we tested the idea that novel aspects of steroid action can be identified through spatial correlation of steroid receptors with genome-wide mRNA expression across different regions in the mouse brain. First, we observed significant coexpression of six nuclear receptors (NRs) [androgen receptor (Ar), estrogen receptor alpha (Esr1), estrogen receptor beta (Esr2), glucocorticoid receptor (Gr), mineralocorticoid receptor (Mr), and progesterone receptor (Pgr)] with sets of steroid target genes that were identified in single brain regions. These coexpression relationships were also present in distinct other brain regions, suggestive of as yet unidentified coordinate regulation of brain regions by, for example, glucocorticoids and estrogens. Second, coexpression of a set of 62 known NR coregulators and the six steroid receptors in 12 nonoverlapping mouse brain regions revealed selective downstream pathways, such as Pak6 as a mediator for the effects of Ar and Gr on dopaminergic transmission. Third, Magel2 and Irs4 were identified and validated as strongly responsive targets to the estrogen diethylstilbestrol in the mouse hypothalamus. The brain- and genome-wide correlations of mRNA expression levels of six steroid receptors that we provide constitute a rich resource for further predictions and understanding of brain modulation by steroid hormones.

scholarly journals Brain geometry matters in Alzheimer’s disease progression: a simulation study

2020 ◽  
Author(s):  
Masoud Hoore ◽  
Jeffrey Kelling ◽  
Mahsa Sayadmanesh ◽  
Tanmay Mitra ◽  
Marta Schips ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Activity ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Brain Regions ◽  
Plaque Formation ◽  
Secretion Rate ◽  
Heterogeneous Distribution ◽  
The Brain

AbstractThe Amyloid cascade hypothesis (ACH) for Alzheimer’s disease (AD) is modeled over the whole brain tissue with a set of partial differential equations. Our results show that the amyloid plaque formation is critically dependent on the secretion rate of amyloid β (Aβ), which is proportional to the product of neural density and neural activity. Neural atrophy is similarly related to the secretion rate of Aβ. Due to a heterogeneous distribution of neural density and brain activity throughout the brain, amyloid plaque formation and neural death occurs heterogeneously in the brain. The geometry of the brain and microglia migration in the parenchyma bring more complexity into the system and result in a diverse amyloidosis and dementia pattern of different brain regions. Although the pattern of amyloidosis in the brain cortex from in-silico results is similar to experimental autopsy findings, they mismatch at the central regions of the brain, suggesting that ACH is not able to explain the whole course of AD without considering other factors, such as tau-protein aggregation or neuroinflammation.

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