scholarly journals Reactive astrocytes augment hippocampal inhibitory tone via GABA transporter-3/4 to facilitate synaptic balance in Alzheimer’s disease

2021 ◽  
Author(s):  
Yousif Aldabbagh ◽  
Anam Islam ◽  
Weicong Zhang ◽  
Paul Whiting ◽  
Afia Ali
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tonic Inhibition ◽  
Reactive Astrocytes ◽  
Post Mortem ◽  
Wild Type ◽  
Gaba Transporter ◽  
Synaptic Excitation ◽  
Post Mortem Brain

Background and Purpose: Cognitive decline is a major symptom in Alzheimer’s disease (AD), which is closely associated with synaptic excitatory-inhibitory imbalance. Here, we investigated whether astrocytic mechanisms involving the astrocyte-specific GABA transporter 3/4 (GAT3/4) play a role in altering the synaptic balance in AD and whether these mechanisms correlate with presynaptic cannabinoid type-1 receptors (CB1-Rs). Experimental approach: Using the APPNL-F/NL-F knock-in mouse model of AD, aged-matched to wild-type mice, we performed in vitro electrophysiological whole-cell recordings combined with immunohistochemistry in the CA1 and dentate gyrus (DG) regions of the hippocampus. Comparative neuroanatomy experiments were also performed in post-mortem brain tissue from human AD patients, age-matched to healthy controls. Results: We observed a higher expression of GABA content and GAT3/4 co-localised with reactive astrocytes, which enhanced tonic inhibition in the CA1, and DG of APPNL-F/NL-F mice compared to the age-matched wild-type animals. Blocking GAT3/4 - associated tonic inhibition in APPNL-F/NL-F mice resulted in an enhanced frequency of synaptic excitation, suggesting a presynaptic mechanism. These data also correlated with an up-regulation of CB1-Rs in astrocytes and cholecystokinin (CCK)-containing interneurons, which also enhanced tonic inhibition in the AD model, but did not affect GAT3/4 -associated tonic inhibition. The neuroanatomical results were mirrored in post-mortem tissue of AD patients. Conclusions: Our data suggest that reactive astrocytes lead to augmented tonic inhibition in the hippocampus, which probably plays an important presynaptic compensatory role in attempting to restore AD-associated neuronal hyperactivity. Therefore, reducing tonic inhibition through GAT3/4 may not be a good therapeutic strategy for AD.

P1-155: Post-Mortem Brain Tissue Characterisation of Inflammatory and Pathological Hallmarks of Alzheimer’s Disease During Disease Progression

2016 ◽  
Vol 12 ◽  
pp. P462-P462
Author(s):  
Martina M. Hughes ◽  
Beatriz G. Perez-Nievas ◽  
Claire Troakes ◽  
Michael Perkinton ◽  
Diane P. Hanger ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Progression ◽  
Brain Tissue ◽  
Post Mortem ◽  
Tissue Characterisation ◽  
Post Mortem Brain

scholarly journals Natriuretic Peptides in Post-mortem Brain Tissue and Cerebrospinal Fluid of Non-demented Humans and Alzheimer’s Disease Patients

2018 ◽  
Vol 12 ◽  
Author(s):  
Simin Mahinrad ◽  
Marjolein Bulk ◽  
Isabelle van der Velpen ◽  
Ahmed Mahfouz ◽  
Willeke van Roon-Mom ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Brain Tissue ◽  
Natriuretic Peptides ◽  
Post Mortem ◽  
Post Mortem Brain

Genome-wide profiling and predicted significance of post-mortem brain microRNA in Alzheimer’s disease

2020 ◽  
Vol 191 ◽  
pp. 111352
Author(s):  
Adriane D. Henriques ◽  
Wilcelly Machado-Silva ◽  
Renata E.P. Leite ◽  
Claudia K. Suemoto ◽  
Kátia R.M. Leite ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Post Mortem ◽  
Genome Wide ◽  
Post Mortem Brain

scholarly journals Molecular signatures in post-mortem brain tissue of younger individuals at high risk for Alzheimer's disease as based on APOE genotype

2010 ◽  
Vol 16 (8) ◽  
pp. 836-847 ◽  
Author(s):  
C Conejero-Goldberg ◽  
T M Hyde ◽  
S Chen ◽  
U Dreses-Werringloer ◽  
M M Herman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
High Risk ◽  
Brain Tissue ◽  
Apoe Genotype ◽  
Molecular Signatures ◽  
Post Mortem ◽  
Post Mortem Brain

scholarly journals Flow-cytometric microglial sorting coupled with quantitative proteomics identifies moesin as a highly-abundant microglial protein with relevance to Alzheimer’s disease

2019 ◽  
Author(s):  
Sruti Rayaprolu ◽  
Tianwen Gao ◽  
Hailian Xiao ◽  
Supriya Ramesha ◽  
Laura D. Weinstock ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Sorting ◽  
Ribosomal Proteins ◽  
Molecular Mechanisms ◽  
Synaptic Proteins ◽  
Wild Type ◽  
Proteomic Data ◽  
Core Set

AbstractBackgroundProteomic characterization of microglia provides the most proximate assessment of functionally relevant molecular mechanisms of neuroinflammation. However, microglial proteomics studies have been limited by low cellular yield and contamination by non-microglial proteins using existing enrichment strategies.MethodsWe coupled magnetic-activated cell sorting (MACS) and fluorescence activated cell sorting (FACS) of microglia with tandem mass tag-mass spectrometry (TMT-MS) to obtain a highly-pure microglial proteome and identified a core set of highly-abundant microglial proteins in adult mouse brain. We interrogated existing human proteomic data for Alzheimer’s disease (AD) relevance of highly-abundant microglial proteins and performed immuno-histochemical and in-vitro validation studies.ResultsQuantitative multiplexed proteomics by TMT-MS of CD11b+ MACS-enriched (N = 5 mice) and FACS-isolated (N = 5 mice), from adult wild-type mice, identified 1,791 proteins. A total of 203 proteins were highly abundant in both datasets, representing a core-set of highly abundant microglial proteins. In addition, we found 953 differentially enriched proteins comparing MACS and FACS-based approaches, indicating significant differences between both strategies. The FACS-isolated microglia proteome was enriched with cytosolic, endoplasmic reticulum, and ribosomal proteins involved in protein metabolism and immune system functions, as well as an abundance of canonical microglial proteins. Conversely, the MACS-enriched microglia proteome was enriched with mitochondrial and synaptic proteins and higher abundance of neuronal, oligodendrocytic and astrocytic proteins. From the 203 consensus microglial proteins with high abundance in both datasets, we confirmed microglial expression of moesin (Msn) in wild-type and 5xFAD mouse brains as well as in human AD brains. Msn expression is nearly exclusively found in microglia that surround Aβ plaques in 5xFAD brains. In in-vitro primary microglial studies, Msn silencing by siRNA decreased Aβ phagocytosis and increased lipopolysaccharide-induced production of the pro-inflammatory cytokine, tumor necrosis factor (TNF). In network analysis of human brain proteomic data, Msn was a hub protein of an inflammatory co-expression module positively associated with AD neuropathological features and cognitive dysfunction.ConclusionsUsing FACS coupled with TMT-MS as the method of choice for microglial proteomics, we define a core set of highly-abundant adult microglial proteins. Among these, we validate Msn as highly-abundant in plaque-associated microglia with relevance to human AD.

scholarly journals Platelet phosphorylated TDP-43: An exploratory study for a peripheral surrogate biomarker development for Alzheimer’s disease

2017 ◽  
Author(s):  
Rodger Wilhite ◽  
Jessica Sage ◽  
Abdurrahman Bouzid ◽  
Tyler Primavera ◽  
Abdulbaki Agbas
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Clinical Signs ◽  
Brain Regions ◽  
Post Mortem ◽  
Disease Prognosis ◽  
Post Mortem Brain ◽  
And Control ◽  
Lateral Sclerosis

AbstractAim: Alzheimer’s disease (AD) and other forms of dementia create a non-curable disease population in World’s societies. To develop a blood-based biomarker is important so that the remedial or disease-altering therapeutic intervention for AD patients would be available at the early stage. Materials & Methods: TDP-43 levels were analyzed in post-mortem brain tissue and platelets of AD and control subjects. Results: We observed an increased TDP-43 (<60%) in post-mortem AD brain regions and similar trends were also observed in patient’s platelets. Conclusion: Platelet TDP-43 could be used as a surrogate biomarker that is measurable, reproducible, and sensitive for screening the patients with some early clinical signs of AD and can be used to monitor disease prognosis.Lay abstractIn this study, we explore to identify an Alzheimer’s disease-selective phospho-specific antibody that recognizes the diseased form of TDP-43 protein in patient’s blood-derived platelets. Our results suggest that selective anti-phosphorylated TDP-43 antibody discriminates Alzheimer’s disease from non-demented controls and patients with amyotrophic lateral sclerosis. Therefore, platelet screening with a selective antibody could potentially be a useful tool for diagnostic purposes for Alzheimer’s disease.

scholarly journals Accelerated loss of hypoxia response in zebrafish with familial Alzheimer’s disease-like mutation of Presenilin 1

2019 ◽  
Author(s):  
Morgan Newman ◽  
Hani Moussavi Nik ◽  
Greg T. Sutherland ◽  
Nhi Hin ◽  
Woojin S. Kim ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Acute Hypoxia ◽  
Presenilin 1 ◽  
Post Mortem ◽  
Wild Type ◽  
Hypoxia Response ◽  
Brain Responses ◽  
Allele Expression ◽  
Age Dependent

AbstractAgeing is the major risk factor for Alzheimer’s disease (AD), a condition involving brain hypoxia. The majority of early onset familial AD (EOfAD) cases involve dominant mutations in the gene PSEN1. PSEN1 null mutations do not cause EOfAD. We exploited putative hypomorphic and EOfAD-like mutations in the zebrafish psen1 gene to explore the effects of age and genotype on brain responses to acute hypoxia. Both mutations accelerate age-dependent changes in hypoxia-sensitive gene expression supporting that ageing is necessary, but insufficient, for AD occurrence. Curiously, the responses to acute hypoxia become inverted in extremely aged fish. This is associated with an apparent inability to upregulate glycolysis. Wild type PSEN1 allele expression is reduced in post-mortem brains of human EOfAD mutation carriers (and extremely aged fish), possibly contributing to EOfAD pathogenesis. We also observed that age-dependent loss of HIF1 stabilisation under hypoxia is a phenomenon conserved across vertebrate classes.

Altered expression of tau exon 10, clk2 and htra2-ß in post mortem brain of patients with Alzheimer’s disease

2004 ◽  
Vol 36 (05) ◽  
Author(s):  
D Glatz ◽  
F Berendt ◽  
F Faltraco ◽  
AM Hartmann ◽  
H Hampel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Post Mortem ◽  
Altered Expression ◽  
Post Mortem Brain ◽  
Exon 10

scholarly journals Impaired Expression of GABA Signaling Components in the Alzheimer’s Disease Middle Temporal Gyrus

2020 ◽  
Vol 21 (22) ◽  
pp. 8704
Author(s):  
Karan Govindpani ◽  
Clinton Turner ◽  
Henry J. Waldvogel ◽  
Richard L. M. Faull ◽  
Andrea Kwakowsky
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gabab Receptor ◽  
Neurodegenerative Disorder ◽  
Middle Temporal Gyrus ◽  
Post Mortem ◽  
Gaba Transporter ◽  
Middle Temporal ◽  
Gaba Signaling ◽  
Signaling Components

γ-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter, playing a central role in the regulation of cortical excitability and the maintenance of the excitatory/inhibitory (E/I) balance. Several lines of evidence point to a remodeling of the cerebral GABAergic system in Alzheimer’s disease (AD), with past studies demonstrating alterations in GABA receptor and transporter expression, GABA synthesizing enzyme activity and focal GABA concentrations in post-mortem tissue. AD is a chronic neurodegenerative disorder with a poorly understood etiology and the temporal cortex is one of the earliest regions in the brain to be affected by AD neurodegeneration. Utilizing NanoString nCounter analysis, we demonstrate here the transcriptional downregulation of several GABA signaling components in the post-mortem human middle temporal gyrus (MTG) in AD, including the GABAA receptor α1, α2, α3, α5, β1, β2, β3, δ, γ2, γ3, and θ subunits and the GABAB receptor 2 (GABABR2) subunit. In addition to this, we note the transcriptional upregulation of the betaine-GABA transporter (BGT1) and GABA transporter 2 (GAT2), and the downregulation of the 67 kDa isoform of glutamate decarboxylase (GAD67), the primary GABA synthesizing enzyme. The functional consequences of these changes require further investigation, but such alterations may underlie disruptions to the E/I balance that are believed to contribute to cognitive decline in AD.

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