scholarly journals Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer’s disease

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Akira Sobue ◽  
Okiru Komine ◽  
Yuichiro Hara ◽  
Fumito Endo ◽  
Hiroyuki Mizoguchi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rna Sequencing ◽  
Mouse Models ◽  
Expression Patterns ◽  
Substantial Reduction ◽  
Neuronal Cell ◽  
Cell Loss ◽  
Amyloid Pathology ◽  
Neuronal Cell Loss

AbstractMicroglia-mediated neuroinflammation has been implicated in the pathogenesis of Alzheimer’s disease (AD). Although microglia in aging and neurodegenerative disease model mice show a loss of homeostatic phenotype and activation of disease-associated microglia (DAM), a correlation between those phenotypes and the degree of neuronal cell loss has not been clarified. In this study, we performed RNA sequencing of microglia isolated from three representative neurodegenerative mouse models, AppNL-G-F/NL-G-F with amyloid pathology, rTg4510 with tauopathy, and SOD1G93A with motor neuron disease by magnetic activated cell sorting. In parallel, gene expression patterns of the human precuneus with early Alzheimer’s change (n = 11) and control brain (n = 14) were also analyzed by RNA sequencing. We found that a substantial reduction of homeostatic microglial genes in rTg4510 and SOD1G93A microglia, whereas DAM genes were uniformly upregulated in all mouse models. The reduction of homeostatic microglial genes was correlated with the degree of neuronal cell loss. In human precuneus with early AD pathology, reduced expression of genes related to microglia- and oligodendrocyte-specific markers was observed, although the expression of DAM genes was not upregulated. Our results implicate a loss of homeostatic microglial function in the progression of AD and other neurodegenerative diseases. Moreover, analyses of human precuneus also suggest loss of microglia and oligodendrocyte functions induced by early amyloid pathology in human.

scholarly journals Meox2 haploinsufficiency increases neuronal cell loss in a mouse model of Alzheimer's disease

2016 ◽  
Vol 42 ◽  
pp. 50-60 ◽  
Author(s):  
Ileana Soto ◽  
Weronika A. Grabowska ◽  
Kristen D. Onos ◽  
Leah C. Graham ◽  
Harriet M. Jackson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Neuronal Cell ◽  
Cell Loss ◽  
Model Of Alzheimer’S Disease ◽  
Neuronal Cell Loss

The role of neuroglial metabotropic glutamate receptors in Alzheimer's disease

2021 ◽  
Vol 19 ◽  
Author(s):  
Khaled S. Abd-Elrahman ◽  
Shaarika Sarasija ◽  
Stephen S. G. Ferguson
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Expression Patterns ◽  
Neuronal Cell ◽  
Hyperphosphorylated Tau ◽  
Metabotropic Glutamate ◽  
Group I ◽  
The Brain

: Glutamate, the major excitatory neurotramitter in the brain exerts its effects via both ionotropic glutamate receptors and metabotropic glutamate receptors (mGluRs). There are three subgroups of mGluRs, pre-synaptic Group II and Group III mGluRs and post-synaptic Group I mGluRs. mGluRs are ubiquitously expressed in the brain and their activation is poised upstream of a myriad of signaling pathways, resulting in their implication in the pathogenesis of various neurodegenerative diseases including, Alzheimer’s disease (AD). While the exact mechanism of AD etiology remains elusive, β-amyloid (Aβ) plaques and hyperphosphorylated tau tangles remain the histopathological hallmarks of AD. Though less electrically excitable, neuroglia are a major non-neuronal cell type in the brain and are composed of astrocytes, microglia, and oligodendrocytes. Astrocytes, microglia, and oligodendrocytes provide structural and metabolic support, active immune defence, and axonal support and sheathing, respectively. Interestingly, Aβ and hyperphosphorylated tau are known to disrupt the neuroglial homeostasis in the brain, pushing them towards a more neurotoxic state. In this review, we discuss what is currently known regarding the expression patterns of various mGluRs in neuroglia and how Aβ and tau alter the normal mGluR function in the neuroglia and contribute to the pathophysiology of AD.

scholarly journals Imaging noradrenergic influence on amyloid pathology in mouse models of Alzheimer’s disease

2008 ◽  
Vol 35 (S1) ◽  
pp. 107-113 ◽  
Author(s):  
A. Winkeler ◽  
Y. Waerzeggers ◽  
A. Klose ◽  
P. Monfared ◽  
A. V. Thomas ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Amyloid Pathology

scholarly journals TNF-α-dependent neuronal necroptosis regulated in Alzheimer's disease by coordination of RIPK1-p62 complex with autophagic UVRAG

2021 ◽  
Author(s):  
Chong Xu ◽  
Jialin Wu ◽  
Yiqun Wu ◽  
Zhichu Ren ◽  
Yuyuan Yao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Neuronal Cell ◽  
Neutralizing Antibody ◽  
Signaling Crosstalk ◽  
Tnf Α ◽  
Smac Mimetic ◽  
Approaches To Study

Abstract Background Neuronal death is a major hallmark of Alzheimer’s disease (AD). Necroptosis, as a programmed necrotic process, is activated in AD. However, what signals and factors initiate necroptosis in AD is basically unknown. Methods We examined the expression levels of critical molecules in necroptotic signaling pathway by immunohistochemistry (IHC) staining and immunoblotting using brain tissues from AD patients and AD mouse models of APP/PS1 and 5×FAD. We performed brain stereotaxic injection with recombinant TNF-α, anti-TNFR1 neutralizing antibody or AAV-mediated gene expression and knockdown in APP/PS1 brains. For in vitro studies, we used TNF-α combined with zVAD-fmk and Smac mimetic to establish neuronal necroptosis models and utilized pharmacological or molecular biological approaches to study the signaling crosstalk.Results We find that activated neuronal necroptosis is dependent on upstream TNF-α/TNFR1 signaling in both neuronal cell cultures and AD mouse models. Upon TNF-α stimulation, accumulated p62 recruits RIPK1 and induces its self-oligomerization, and activates downstream RIPK1/RIPK3/MLKL cascade, leading to neuronal necroptosis. We further reveal that ectopic accumulation of p62 is caused by impaired autophagy flux, which is mediated by downregulation of UVRAG during the TNF-α-promoted necroptosis. Notably, UVRAG overexpression can inhibit neuronal necroptosis in cultures and in brains of AD mice. Conclusions We identify a finely controlled regulation of neuronal necroptosis in AD by coordinated TNF-α signaling, RIPK1/3 activity and autophagy machinery.

scholarly journals Does Chronic Sleep Fragmentation Lead to Alzheimer's Disease in Young Wild-Type Mice?

2021 ◽  
Vol 13 ◽  
Author(s):  
Li Ba ◽  
Lifang Huang ◽  
Ziyu He ◽  
Saiyue Deng ◽  
Yi Xie ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glucose Metabolism ◽  
Differential Expression ◽  
Mouse Models ◽  
Neurological Diseases ◽  
Expression Patterns ◽  
Sleep Fragmentation ◽  
Wild Type ◽  
Chronic Sleep

Chronic sleep insufficiency is becoming a common issue in the young population nowadays, mostly due to life habits and work stress. Studies in animal models of neurological diseases reported that it would accelerate neurodegeneration progression and exacerbate interstitial metabolic waste accumulation in the brain. In this paper, we study whether chronic sleep insufficiency leads to neurodegenerative diseases in young wild-type animals without a genetic pre-disposition. To this aim, we modeled chronic sleep fragmentation (SF) in young wild-type mice. We detected pathological hyperphosphorylated-tau (Ser396/Tau5) and gliosis in the SF hippocampus. 18F-labeled fluorodeoxyglucose positron emission tomography scan (18F-FDG-PET) further revealed a significant increase in brain glucose metabolism, especially in the hypothalamus, hippocampus and amygdala. Hippocampal RNAseq indicated that immunological and inflammatory pathways were significantly altered in 1.5-month SF mice. More interestingly, differential expression gene lists from stress mouse models showed differential expression patterns between 1.5-month SF and control mice, while Alzheimer's disease, normal aging, and APOEε4 mutation mouse models did not exhibit any significant pattern. In summary, 1.5-month sleep fragmentation could generate AD-like pathological changes including tauopathy and gliosis, mainly linked to stress, as the incremented glucose metabolism observed with PET imaging suggested. Further investigation will show whether SF could eventually lead to chronic neurodegeneration if the stress condition is prolonged in time.

scholarly journals 387. Gene Delivery of APOE2 Reduces Amyloid Pathology in Transgenic Mouse Models of Alzheimer's Disease

2015 ◽  
Vol 23 ◽  
pp. S154
Author(s):  
Lingzhi Zhao ◽  
Andrew J. Gottesdiener ◽  
Mayur Parmar ◽  
Christine Grevstad ◽  
David Havlicek ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gene Delivery ◽  
Transgenic Mouse ◽  
Mouse Models ◽  
Transgenic Mouse Models ◽  
Amyloid Pathology
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