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.

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

2020 ◽  
Vol 29 (14) ◽  
pp. 2379-2394 ◽  
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 ◽  
Wild Type ◽  
Hypoxia Response ◽  
Brain Responses ◽  
Allele Expression ◽  
Age Dependent ◽  
Psen1 Gene

Abstract Ageing 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 stabilization under hypoxia is a phenomenon conserved across vertebrate classes.

scholarly journals Processing of Wild-Type and Mutant Familial Alzheimer’s Disease-Associated Presenilin-1 in Cultured Neurons

2004 ◽  
Vol 73 (1) ◽  
pp. 31-40 ◽  
Author(s):  
Conrad C. Weihl ◽  
Ghanaysham D. Ghadge ◽  
Richard J. Miller ◽  
Raymond P. Roos
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Presenilin 1 ◽  
Cultured Neurons ◽  
Wild Type ◽  
Familial Alzheimer’S Disease ◽  
Familial Alzheimer's Disease

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.

scholarly journals Neural oscillations during cognitive processes in an App knock-in mouse model of Alzheimer’s disease pathology

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Sofia Jacob ◽  
Gethin Davies ◽  
Marijke De Bock ◽  
Bart Hermans ◽  
Cindy Wintmolders ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Home Environment ◽  
Amyloid Β ◽  
Wild Type ◽  
Model Of Alzheimer’S Disease ◽  
Age Dependent ◽  
In The Wild ◽  
Phase Amplitude

Abstract Multiple animal models have been created to gain insight into Alzheimer’s disease (AD) pathology. Among the most commonly used models are transgenic mice overexpressing human amyloid precursor protein (APP) with mutations linked to familial AD, resulting in the formation of amyloid β plaques, one of the pathological hallmarks observed in AD patients. However, recent evidence suggests that the overexpression of APP by itself can confound some of the reported observations. Therefore, we investigated in the present study the AppNL-G-Fmodel, an App knock-in (App-KI) mouse model that develops amyloidosis in the absence of APP-overexpression. Our findings at the behavioral, electrophysiological, and histopathological level confirmed an age-dependent increase in Aβ1–42 levels and plaque deposition in these mice in accordance with previous reports. This had apparently no consequences on cognitive performance in a visual discrimination (VD) task, which was largely unaffected in AppNL-G-F mice at the ages tested. Additionally, we investigated neurophysiological functioning of several brain areas by phase-amplitude coupling (PAC) analysis, a measure associated with adequate cognitive functioning, during the VD task (starting at 4.5 months) and the exploration of home environment (at 5 and 8 months of age). While we did not detect age-dependent changes in PAC during home environment exploration for both the wild-type and the AppNL-G-F mice, we did observe subtle changes in PAC in the wild-type mice that were not present in the AppNL-G-F mice.

scholarly journals Impacts of Acute Hypoxia on Alzheimer's Disease-Like Pathologies in APPswe/PS1dE9 Mice and Their Wild Type Littermates

2018 ◽  
Vol 12 ◽  
Author(s):  
Feng Zhang ◽  
Rujia Zhong ◽  
Hongqian Qi ◽  
Song Li ◽  
Cheng Cheng ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Acute Hypoxia ◽  
Wild Type

Tau phosphorylation in cells transfected with wild-type or an Alzheimer's disease mutant Presenilin 1

1997 ◽  
Vol 222 (2) ◽  
pp. 71-74 ◽  
Author(s):  
Nicholas G Irving ◽  
Christopher C.J Miller
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Phosphorylation ◽  
Presenilin 1 ◽  
Wild Type ◽  
In Cells

scholarly journals Generation of a humanized Aβ expressing mouse demonstrating aspects of Alzheimer’s disease-like pathology

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
David Baglietto-Vargas ◽  
Stefania Forner ◽  
Lena Cai ◽  
Alessandra C. Martini ◽  
Laura Trujillo-Estrada ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Autosomal Dominant ◽  
Late Onset ◽  
Periodic Acid ◽  
Wild Type ◽  
Periodic Acid Schiff ◽  
Human Counterpart ◽  
Age Dependent

AbstractThe majority of Alzheimer’s disease (AD) cases are late-onset and occur sporadically, however most mouse models of the disease harbor pathogenic mutations, rendering them better representations of familial autosomal-dominant forms of the disease. Here, we generated knock-in mice that express wildtype human Aβ under control of the mouse App locus. Remarkably, changing 3 amino acids in the mouse Aβ sequence to its wild-type human counterpart leads to age-dependent impairments in cognition and synaptic plasticity, brain volumetric changes, inflammatory alterations, the appearance of Periodic Acid-Schiff (PAS) granules and changes in gene expression. In addition, when exon 14 encoding the Aβ sequence was flanked by loxP sites we show that Cre-mediated excision of exon 14 ablates hAβ expression, rescues cognition and reduces the formation of PAS granules.

scholarly journals Acute Hypoxia Induced an Imbalanced M1/M2 Activation of Microglia through NF-κB Signaling in Alzheimer’s Disease Mice and Wild-Type Littermates

2017 ◽  
Vol 9 ◽  
Author(s):  
Feng Zhang ◽  
Rujia Zhong ◽  
Song Li ◽  
Zhenfa Fu ◽  
Cheng Cheng ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Acute Hypoxia ◽  
Wild Type

scholarly journals A familial Alzheimer's disease-like mutation in the zebrafish presenilin 1 gene affects brain energy production

2019 ◽  
Author(s):  
Morgan Newman ◽  
Nhi Hin ◽  
Stephen M Pederson ◽  
Michael Lardelli
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Atp Synthesis ◽  
Orthologous Gene ◽  
Presenilin 1 ◽  
Wild Type ◽  
Vacuolar Acidification ◽  
Dependent Processes ◽  
Brain Energy ◽  
Detailed Molecular Analysis

To prevent or ameliorate Alzheimer's disease (AD) we must understand its molecular basis. AD develops over decades but detailed molecular analysis of AD brains is limited to postmortem tissue where the stresses initiating the disease may be obscured by compensatory responses and neurodegenerative processes. Rare, dominant mutations in a small number of genes, but particularly the gene PRESENILIN 1 (PSEN1), drive early onset of familial AD (EOfAD). Numerous transgenic models of AD have been constructed in mouse and other organisms, but transcriptomic analysis of these models has raised serious doubts regarding their representation of the disease state. Since we lack clarity regarding the molecular mechanism(s) underlying AD, we posit that the most valid approach is to model the human EOfAD genetic state as closely as possible. Therefore, we sought to analyse brains from zebrafish heterozygous for a single, EOfAD-like mutation in their PSEN1-orthologous gene, psen1. We previously introduced an EOfAD-like mutation (Q96_K97del) into the endogenous psen1 gene of zebrafish. Here, we analysed transcriptomes of young adult (6-month-old) entire brains from a family of heterozygous mutant and wild type sibling fish. Gene ontology (GO) analysis revealed effects on mitochondria, particularly ATP synthesis, and on ATP-dependent processes including vacuolar acidification.

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