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.

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 No observed effect on brain vasculature of Alzheimer’s disease-related mutations in the zebrafish presenilin 1 gene

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Karissa Barthelson ◽  
Morgan Newman ◽  
Cameron J. Nowell ◽  
Michael Lardelli
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Presenilin 1 ◽  
Hypoxic Stress ◽  
Adult Zebrafish ◽  
Wild Type ◽  
Vascular Morphology ◽  
Brain Vasculature ◽  
Basal Expression ◽  
Density Surface

AbstractPreviously, we found that brains of adult zebrafish heterozygous for Alzheimer’s disease-related mutations in their presenilin 1 gene (psen1, orthologous to human PSEN1) show greater basal expression levels of hypoxia responsive genes relative to their wild type siblings under normoxia, suggesting hypoxic stress. In this study, we investigated whether this might be due to changes in brain vasculature. We generated and compared 3D reconstructions of GFP-labelled blood vessels of the zebrafish forebrain from heterozygous psen1 mutant zebrafish and their wild type siblings. We observed no statistically significant differences in vessel density, surface area, overall mean diameter, overall straightness, or total vessel length normalised to the volume of the telencephalon. Our findings do not support that changes in vascular morphology are responsible for the increased basal expression of hypoxia responsive genes in psen1 heterozygous mutant brains.

Depressive Symptoms and APOE ε2 Broad the Natural History in Presenilin-1 E280A Familial Early-Onset Alzheimer's Disease

2018 ◽  
Author(s):  
Natalia Acosta-Baena ◽  
Carlos Mario Lopera-Gómez ◽  
Mario César Jaramillo-Elorza ◽  
Margarita Giraldo-Chica ◽  
Mauricio Arcos-Burgos ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Depressive Symptoms ◽  
Natural History ◽  
Early Onset ◽  
Presenilin 1 ◽  
Early Onset Alzheimer’S Disease
Sign in / Sign up

Export Citation Format

Share Document