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.

Genetics, Alzheimer's Disease and Senile Dementia

1989 ◽  
Vol 154 (3) ◽  
pp. 311-320 ◽  
Author(s):  
D. W. K. Kay
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Old Age ◽  
Autosomal Dominant ◽  
Late Onset ◽  
Senile Dementia ◽  
Twin Studies ◽  
Age Dependent ◽  
Competing Causes

Genetic factors in the aetiology of Alzheimer's disease (AD), are now being intensively investigated. The homogeneity of AD is under investigation. There are a few large kindreds with early onset of AD in whom transmission appears to be typically autosomal dominant, and 65% or more of the remaining cases at any age may have genetic aetiology. Both multifactorial and autosomal dominant inheritance with age-dependent expression have been proposed, but the late onset and death of unaffected relatives from competing causes make it difficult to choose between them. Lifetime risk gives the best estimate of incidence in family studies, but clinical and pathological criteria are not clear enough for confident diagnosis of AD in late old age. A role for external factors is indicated by twin studies, and the role of aluminium is currently under investigation. Molecular genetics promises to resolve many questions. The clinicians' role will be to provide well documented families for interdisciplinary research and to help in clarifying diagnosis in late old age.

scholarly journals Transcriptome analyses of 7-day-old zebrafish larvae possessing a familial Alzheimer’s disease-like mutation in psen1 indicate effects on oxidative phosphorylation, ECM and MCM functions, and iron homeostasis

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Yang Dong ◽  
Morgan Newman ◽  
Stephen M. Pederson ◽  
Karissa Barthelson ◽  
Nhi Hin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Oxidative Phosphorylation ◽  
Transcriptome Analysis ◽  
Iron Homeostasis ◽  
Late Onset ◽  
Wild Type ◽  
Familial Alzheimer’S Disease ◽  
Zebrafish Larvae ◽  
Familial Alzheimer's Disease

Abstract Background Early-onset familial Alzheimer’s disease (EOfAD) is promoted by dominant mutations, enabling the study of Alzheimer’s disease (AD) pathogenic mechanisms through generation of EOfAD-like mutations in animal models. In a previous study, we generated an EOfAD-like mutation, psen1Q96_K97del, in zebrafish and performed transcriptome analysis comparing entire brains from 6-month-old wild type and heterozygous mutant fish. We identified predicted effects on mitochondrial function and endolysosomal acidification. Here we aimed to determine whether similar effects occur in 7 day post fertilization (dpf) zebrafish larvae that might be exploited in screening of chemical libraries to find ameliorative drugs. Results We generated clutches of wild type and heterozygous psen1Q96_K97del 7 dpf larvae using a paired-mating strategy to reduce extraneous genetic variation before performing a comparative transcriptome analysis. We identified 228 differentially expressed genes and performed various bioinformatics analyses to predict cellular functions. Conclusions Our analyses predicted a significant effect on oxidative phosphorylation, consistent with our earlier observations of predicted effects on ATP synthesis in adult heterozygous psen1Q96_K97del brains. The dysregulation of minichromosome maintenance protein complex (MCM) genes strongly contributed to predicted effects on DNA replication and the cell cycle and may explain earlier observations of genome instability due to PSEN1 mutation. The upregulation of crystallin gene expression may be a response to defective activity of mutant Psen1 protein in endolysosomal acidification. Genes related to extracellular matrix (ECM) were downregulated, consistent with previous studies of EOfAD mutant iPSC neurons and postmortem late onset AD brains. Also, changes in expression of genes controlling iron ion transport were observed without identifiable changes in the prevalence of transcripts containing iron responsive elements (IREs) in their 3′ untranslated regions (UTRs). These changes may, therefore, predispose to the apparent iron dyshomeostasis previously observed in 6-month-old heterozygous psen1Q96_K97del EOfAD-like mutant brains.

scholarly journals The Clinical and Neuropathological Features of Sporadic (Late-Onset) and Genetic Forms of Alzheimer’s Disease

2021 ◽  
Vol 10 (19) ◽  
pp. 4582
Author(s):  
Tanzil Rujeedawa ◽  
Eva Carrillo Félez ◽  
Isabel C. H. Clare ◽  
Juan Fortea ◽  
Andre Strydom ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Autosomal Dominant ◽  
Late Onset ◽  
Prodromal Phase ◽  
Phenotypic Differences ◽  
Autosomal Dominant Alzheimer’S Disease ◽  
Neurological Features

The purpose of this review is to compare and highlight the clinical and pathological aspects of genetic versus acquired Alzheimer’s disease: Down syndrome-associated Alzheimer’s disease in (DSAD) and Autosomal Dominant Alzheimer’s disease (ADAD) are compared with the late-onset form of the disease (LOAD). DSAD and ADAD present in a younger population and are more likely to manifest with non-amnestic (such as dysexecutive function features) in the prodromal phase or neurological features (such as seizures and paralysis) especially in ADAD. The very large variety of mutations associated with ADAD explains the wider range of phenotypes. In the LOAD, age-associated comorbidities explain many of the phenotypic differences.

O3-04-03: Age-Related Neuropathology Helps Distinguish Autosomal Dominant from Late-Onset Alzheimer's Disease

2016 ◽  
Vol 12 ◽  
pp. P291-P292
Author(s):  
Nigel J. Cairns ◽  
Richard J. Perrin ◽  
Erin E. Franklin ◽  
Benjamin D. Vincent ◽  
Michael Baxter ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Autosomal Dominant ◽  
Late Onset ◽  
Age Related

scholarly journals Integrated DNA methylation and gene expression profiling across multiple brain regions implicate novel genes in Alzheimer’s disease

2018 ◽  
Author(s):  
Stephen A. Semick ◽  
Rahul A. Bharadwaj ◽  
Leonardo Collado-Torres ◽  
Ran Tao ◽  
Joo Heon Shin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Methylation ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Brain Regions ◽  
Epigenetic Mechanism ◽  
Novel Genes ◽  
Age Related

AbstractBackgroundLate-onset Alzheimer’s disease (AD) is a complex age-related neurodegenerative disorder that likely involves epigenetic factors. To better understand the epigenetic state associated with AD represented as variation in DNA methylation (DNAm), we surveyed 420,852 DNAm sites from neurotypical controls (N=49) and late-onset AD patients (N=24) across four brain regions (hippocampus, entorhinal cortex, dorsolateral prefrontal cortex and cerebellum).ResultsWe identified 858 sites with robust differential methylation, collectively annotated to 772 possible genes (FDR<5%, within 10kb). These sites were overrepresented in AD genetic risk loci (p=0.00655), and nearby genes were enriched for processes related to cell-adhesion, immunity, and calcium homeostasis (FDR<5%). We analyzed corresponding RNA-seq data to prioritize 130 genes within 10kb of the differentially methylated sites, which were differentially expressed and had expression levels associated with nearby DNAm levels (p<0.05). This validated gene set includes previously reported (e.g. ANK1, DUSP22) and novel genes involved in Alzheimer’s disease, such as ANKRD30B.ConclusionsThese results highlight DNAm changes in Alzheimer’s disease that have gene expression correlates, implicating DNAm as an epigenetic mechanism underlying pathological molecular changes associated with AD. Furthermore, our framework illustrates the value of integrating epigenetic and transcriptomic data for understanding complex 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.

Novel Late-Onset Alzheimer's Disease Loci Variants Associate with Brain Gene Expression (S54.001)

Neurology ◽  
2012 ◽  
Vol 78 (Meeting Abstracts 1) ◽  
pp. S54.001-S54.001
Author(s):  
M. Allen ◽  
F. Zou ◽  
H. S. Chai ◽  
C. Younkin ◽  
J. Crook ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Brain Gene Expression ◽  
Disease Loci
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