Brain Transcriptome Analysis of a Protein-Truncating Mutation in Sortilin-Related Receptor 1 Associated With Early-Onset Familial Alzheimer’s Disease Indicates Early Effects on Mitochondrial and Ribosome Function

2020 ◽  
pp. 1-15
Author(s):  
Karissa Barthelson ◽  
Stephen Martin Pederson ◽  
Morgan Newman ◽  
Michael Lardelli
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Young Adult ◽  
Early Onset ◽  
Amyloid Β ◽  
Targeted Mutagenesis ◽  
Receptor Protein ◽  
Truncating Mutation ◽  
Brain Transcriptome ◽  
Ribosomal Function

Background: The early cellular stresses leading to Alzheimer’s disease (AD) remain poorly understood because we cannot access living, asymptomatic human AD brains for detailed molecular analyses. Sortilin-related receptor 1 (SORL1) encodes a multi-domain receptor protein genetically associated with both rare, early-onset familial AD (EOfAD) and common, sporadic, late-onset AD (LOAD). SORL1 protein has been shown to act in the trafficking of the amyloid β A4 precursor protein (AβPP) that is proteolysed to form one of the pathological hallmarks of AD, amyloid-β (Aβ) peptide. However, other functions of SORL1 in AD are less well understood. Objective: To investigate the effects of heterozygosity for an EOfAD-like mutation in SORL1 on the brain transcriptome of young-adult mutation carriers using zebrafish as a model organism. Methods: We performed targeted mutagenesis to generate an EOfAD-like mutation in the zebrafish orthologue of SORL1 and performed RNA-sequencing on mRNA isolated from the young adult brains of siblings in a family of fish either wild type (non-mutant) or heterozygous for the EOfAD-like mutation. Results: We identified subtle differences in gene expression indicating changes in mitochondrial and ribosomal function in the mutant fish. These changes appear to be independent of changes in mitochondrial content or the expression of AβPP-related proteins in zebrafish. Conclusion: These findings provided evidence supporting that EOfAD mutations in SORL1 affect mitochondrial and ribosomal function and provide the basis for future investigation elucidating the nature of these effects.

scholarly journals Transcriptome analysis of a protein-truncating mutation in sortilin-related receptor 1 associated with early-onset familial Alzheimer’s disease indicates effects on mitochondrial and ribosome function in young-adult zebrafish brains

2020 ◽  
Author(s):  
Karissa Barthelson ◽  
Stephen Pederson ◽  
Morgan Newman ◽  
Michael Lardelli
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Onset ◽  
Reverse Genetics ◽  
Late Onset ◽  
Model Organism ◽  
Amyloid Β ◽  
Targeted Mutagenesis ◽  
Receptor Protein ◽  
Truncating Mutation

AbstractThe early cellular stresses which eventually lead to Alzheimer’s disease (AD) remain poorly understood because we cannot access living, asymptomatic human AD brains for detailed molecular analyses. Sortilin-related receptor 1 (SORL1) encodes a multi-domain receptor protein genetically associated with both rare, early-onset familial AD (EOfAD) and common, sporadic late-onset AD (LOAD). SORL1 has been shown to play a role in the trafficking of the amyloid β A4 precursor protein (APP) which is cleaved proteolytically to form one of the pathological hallmarks of AD, amyloid β (Aβ) peptide. However, the other functions of SORL1 are less well understood. Here, we employed a reverse genetics approach to characterise the effect of an EOfAD mutation in SORL1 using zebrafish as a model organism. We performed targeted mutagenesis to generate an EOfAD-like mutation in the zebrafish orthologue of SORL1, and performed RNA-sequencing on mRNA isolated from a family of fish either heterozygous for the EOfAD-like mutation or their wild type siblings and identified subtle effects on the expression of genes which likely indicate changes in mitochondrial and ribosomal function. These changes appear to be independent of changes to expression of APP-related proteins in zebrafish, and mitochondrial content.

scholarly journals Case of early-onset Alzheimer’s disease with atypical manifestation

2021 ◽  
Vol 34 (1) ◽  
pp. e100283
Author(s):  
Lin Zhu ◽  
Limin Sun ◽  
Lin Sun ◽  
Shifu Xiao
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Manifestation ◽  
Early Onset ◽  
Short Term Memory ◽  
Brain Mri ◽  
Memory Loss ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Fluent Aphasia

Short-term memory decline is the typical clinical manifestation of Alzheimer’s disease (AD). However, early-onset AD usually has atypical symptoms and may get misdiagnosed. In the present case study, we reported a patient who experienced symptoms of memory loss with progressive non-fluent aphasia accompanied by gradual social withdrawal. He did not meet the diagnostic criteria of AD based on the clinical manifestation and brain MRI. However, his cerebrospinal fluid examination showed a decreased level of beta-amyloid 42, and increased total tau and phosphorylated tau. Massive amyloid β-protein deposition by 11C-Pittsburgh positron emission tomography confirmed the diagnosis of frontal variant AD. This case indicated that early-onset AD may have progressive non-fluent aphasia as the core manifestation. The combination of individual and precision diagnosis would be beneficial for similar cases.

scholarly journals Longitudinal Observation of Early-Onset Alzheimer’s Disease Dementia with Positive CSF Biomarkers/Negative Amyloid-β Positron-Emission Tomography

2021 ◽  
Vol 39 (3) ◽  
pp. 214-218
Author(s):  
Min Hye Kim ◽  
Joonho Lee ◽  
Hong Nam Kim ◽  
In Ja Shin ◽  
Keun Lee ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Positron Emission Tomography ◽  
Early Onset ◽  
Brain Magnetic Resonance Imaging ◽  
Amyloid Β ◽  
Emission Tomography ◽  
Csf Biomarkers ◽  
Amyloid Pet ◽  
Positron Emission

We report a 61-year-old woman with clinical course for Alzheimer’s disease (AD) dementia and discordant amyloid-β positron-emission tomography (PET) and cerebrospinal fluid biomarkers. Brain magnetic resonance imaging revealed remarkable atrophy in the hippocampus. However, repeated delayed <sup>18</sup>F-flutemetamol brain amyloid PET images with 1 year-interval revealed no amyloid deposition, whereas her CSF revealed low Aβ42, high total tau and p-tau181. This discordant amyloid-β PET and CSF biomarkers in this early-onset AD dementia might be associated with her low resilience or mixed pathology.

scholarly journals Genetic dissection of down syndrome-associated alterations in APP/amyloid-β biology using mouse models

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Justin L. Tosh ◽  
◽  
Elena R. Rhymes ◽  
Paige Mumford ◽  
Heather T. Whittaker ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Amyloid Precursor Protein ◽  
Mouse Models ◽  
Early Onset ◽  
Amyloid Β ◽  
Chromosome 21 ◽  
Extra Copy ◽  
Early Onset Alzheimer’S Disease

AbstractIndividuals who have Down syndrome (caused by trisomy of chromosome 21), have a greatly elevated risk of early-onset Alzheimer’s disease, in which amyloid-β accumulates in the brain. Amyloid-β is a product of the chromosome 21 gene APP (amyloid precursor protein) and the extra copy or ‘dose’ of APP is thought to be the cause of this early-onset Alzheimer’s disease. However, other chromosome 21 genes likely modulate disease when in three-copies in people with Down syndrome. Here we show that an extra copy of chromosome 21 genes, other than APP, influences APP/Aβ biology. We crossed Down syndrome mouse models with partial trisomies, to an APP transgenic model and found that extra copies of subgroups of chromosome 21 gene(s) modulate amyloid-β aggregation and APP transgene-associated mortality, independently of changing amyloid precursor protein abundance. Thus, genes on chromosome 21, other than APP, likely modulate Alzheimer’s disease in people who have Down syndrome.

Amyloid β secretase gene (BACE) is neither mutated in nor associated with early-onset Alzheimer's disease

2001 ◽  
Vol 313 (1-2) ◽  
pp. 105-107 ◽  
Author(s):  
Marc Cruts ◽  
Bart Dermaut ◽  
Rosa Rademakers ◽  
Gerwin Roks ◽  
Marleen Van den Broeck ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Onset ◽  
Amyloid Β ◽  
Early Onset Alzheimer’S Disease

scholarly journals Accelerated brain aging towards transcriptional inversion in a zebrafish model of familial Alzheimer’s disease

2018 ◽  
Author(s):  
Nhi Hin ◽  
Morgan Newman ◽  
Jan Kaslin ◽  
Alon M. Douek ◽  
Amanda Lumsden ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Stress Responses ◽  
Early Onset ◽  
Genetic Model ◽  
Brain Aging ◽  
Zebrafish Model ◽  
Oxidative Stresses ◽  
Brain Transcriptome ◽  
The Brain

AbstractAlzheimer’s disease (AD) develops silently over decades. We cannot easily access and analyse pre-symptomatic brains, so the earliest molecular changes that initiate AD remain unclear. Previously, we demonstrated that the genes mutated in early-onset, dominantly-inherited familial forms of AD (fAD) are evolving particularly rapidly in mice and rats. Fortunately, some non-mammalian vertebrates such as the zebrafish preserve fAD-relevant transcript isoforms of the PRESENILIN (PSEN1 and PSEN2) genes that these rodents have lost. Zebrafish are powerful vertebrate genetic models for many human diseases, but no genetic model of fAD in zebrafish currently exists. We edited the zebrafish genome to model the unique, protein-truncating fAD mutation of human PSEN2, K115fs. Analysing the brain transcriptome and proteome of young (6-month-old) and aged, infertile (24-month-old) wild type and heterozygous fAD-like mutant female sibling zebrafish supports accelerated brain aging and increased glucocorticoid signalling in young fAD-like fish, leading to a transcriptional ‘inversion’ into glucocorticoid resistance and vast changes in biological pathways in aged, infertile fAD-like fish. Notably, one of these changes involving microglia-associated immune responses regulated by the ETS transcription factor family is preserved between our zebrafish fAD model and human early-onset AD. Importantly, these changes occur before obvious histopathology and likely in the absence of Aβ. Our results support the contributions of early metabolic and oxidative stresses to immune and stress responses favouring AD pathogenesis and highlight the value of our fAD-like zebrafish genetic model for elucidating early changes in the brain that promote AD pathogenesis. The success of our approach has important implications for future modelling of AD.

scholarly journals Genetic dissection of Down syndrome-associated alterations in APP/amyloid-β biology using mouse models

2020 ◽  
Author(s):  
Justin L. Tosh ◽  
Ellie Rhymes ◽  
Paige Mumford ◽  
Heather T. Whittaker ◽  
Laura J. Pulford ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Amyloid Precursor Protein ◽  
Mouse Models ◽  
Early Onset ◽  
Amyloid Β ◽  
Chromosome 21 ◽  
Extra Copy ◽  
Early Onset Alzheimer’S Disease

AbstractIndividuals who have Down syndrome (caused by trisomy of chromosome 21), have a greatly elevated risk of early-onset Alzheimer’s disease, in which amyloid-β accumulates in the brain. Amyloid-β is a product of the chromosome 21 gene APP (amyloid precursor protein) and the extra copy or ‘dose’ of APP is thought to be the cause of this early-onset Alzheimer’s disease. However, other chromosome 21 genes likely modulate disease when in three-copies in people with Down syndrome. Here we show that an extra copy of chromosome 21 genes, other than APP, influences APP/Aβ biology. We crossed Down syndrome mouse models with partial trisomies, to an APP transgenic model and found that extra copies of subgroups of chromosome 21 gene(s) modulate amyloid-β aggregation and APP transgene-associated mortality, independently of changing amyloid precursor protein abundance. Thus, genes on chromosome 21, other than APP, likely modulate Alzheimer’s disease in people who have Down syndrome.

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