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Authors: Barthelson, Karissa | Newman, Morgan | Lardelli, Michael

Article Type: Review Article

Abstract: Sortilin-related receptor 1 (SORL1) encodes a large, multi-domain containing, membrane-bound receptor involved in endosomal sorting of proteins between the trans-Golgi network, endosomes and the plasma membrane. It is genetically associated with Alzheimer’s disease (AD), the most common form of dementia. SORL1 is a unique gene in AD, as it appears to show strong associations with the common, late-onset, sporadic form of AD and the rare, early-onset familial form of AD. Here, we review the genetics of SORL1 in AD and discuss potential roles it could play in AD pathogenesis.

Keywords: Alzheimer’s disease, amyloid, amyloid-beta protein precursor, endocytosis, endosomes, protein transport

DOI: 10.3233/ADR-200177

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 123-140, 2020

Authors: Jiang, Haowei | Jayadev, Suman | Lardelli, Michael | Newman, Morgan

Article Type: Review Article

Abstract: PRESENILIN 1 (PSEN1 ) and PRESENILIN 2 (PSEN2 ) genes are loci for mutations causing familial Alzheimer’s disease (fAD). However, the function of these genes and how they contribute to fAD pathogenesis has not been fully determined. This review provides a summary of the overlapping and independent functions of the PRESENILINS with a focus on the lesser studied PSEN2 . As a core component of the γ-secretase complex, the PSEN2 protein is involved in many γ-secretase-related physiological activities, including innate immunity, Notch signaling, autophagy, and mitochondrial function. These physiological activities have all been associated with AD progression, indicating that PSEN2 …plays a particular role in AD pathogenesis. Show more

Keywords: Alzheimer’s disease, γ-secretase, PRESENILIN 1, PRESENILIN 2

DOI: 10.3233/JAD-180656

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1323-1339, 2018

Authors: Newman, Morgan | Tucker, Ben | Nornes, Svanhild | Ward, Alister | Lardelli, Michael

Article Type: Research Article

Abstract: Aberrant splicing and point mutations in the human presenilin genes, PSEN1 and PSEN2, have been linked to familial forms of Alzheimer's disease. We have previously described that low-level aberrant splicing of exon 8 in zebrafish psen1 transcripts in zebrafish embryos produces potent dominant negative effects that increase psen1 transcription, cause a dramatic hydrocephalus phenotype, decreased pigmentation and other developmental defects. Similar effects are also observed after low-level interference with splicing of exon 8 of psen2. To determine the molecular etiology of these effects, we performed microarray analyses of global gene expression changes. Of the 100 genes that showed greatest dysregulation …after either psen1 or psen2 manipulation, 12 genes were common to both treatments. Five of these have known function and showed increased expression: cyclin G1 (ccng1), prosaposin (psap), cathepsin Lb (ctslb), heat shock protein 70kDa (hsp70) and hatching enzyme 1 (he1). We used phylogenetic and conserved synteny analysis to confirm the orthology of zebrafish ccng1 with human CCNG1. We analyzed the expression of zebrafish ccng1 in developing embryos to 24 hours post fertilization (hpf). Decreased ccng1 expression does not rescue the hydrocephalus or pigmentation phenotypes of embryos with aberrant splicing of psen1 exon 8. Show more

Keywords: Alzheimer's disease, cyclin G1, presenilin, prosaposin, zebrafish

DOI: 10.3233/JAD-2009-0945

Citation: Journal of Alzheimer's Disease, vol. 16, no. 1, pp. 133-147, 2009

Authors: Barthelson, Karissa | Pederson, Stephen Martin | Newman, Morgan | Lardelli, Michael

Article Type: Research Article

Abstract: 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. Show more

Keywords: Alzheimer’s disease, mitochondria, ribosome, RNA-seq, sorl1, zebrafish

DOI: 10.3233/JAD-201383

Citation: Journal of Alzheimer's Disease, vol. 79, no. 3, pp. 1105-1119, 2021

Authors: Barthelson, Karissa | Dong, Yang | Newman, Morgan | Lardelli, Michael

Article Type: Research Article

Abstract: Background: The most common cause of early-onset familial Alzheimer’s disease (EOfAD) is mutations in PRESENILIN 1 (PSEN1 ) allowing production of mRNAs encoding full-length, but mutant, proteins. In contrast, a single known frameshift mutation in PSEN1 causes familial acne inversa (fAI) without EOfAD. The molecular consequences of heterozygosity for these mutation types, and how they cause completely different diseases, remains largely unexplored. Objective: To analyze brain transcriptomes of young adult zebrafish to identify similarities and differences in the effects of heterozygosity for psen1 mutations causing EOfAD or fAI. Methods: RNA sequencing was performed on mRNA isolated from the brains of …a single family of 6-month-old zebrafish siblings either wild type or possessing a single, heterozygous EOfAD-like or fAI-like mutation in their endogenous psen1 gene. Results: Both mutations downregulate genes encoding ribosomal subunits, and upregulate genes involved in inflammation. Genes involved in energy metabolism appeared significantly affected only by the EOfAD-like mutation, while genes involved in Notch, Wnt and neurotrophin signaling pathways appeared significantly affected only by the fAI-like mutation. However, investigation of direct transcriptional targets of Notch signaling revealed possible increases in γ -secretase activity due to heterozygosity for either psen1 mutation. Transcriptional adaptation due to the fAI-like frameshift mutation was evident. Conclusion: We observed both similar and contrasting effects on brain transcriptomes of the heterozygous EOfAD-like and fAI-like mutations. The contrasting effects may illuminate how these mutation types cause distinct diseases. Show more

Keywords: Alzheimer’s disease, acne inversa, gamma-secretase, Presenilin 1, RNA-seq, zebrafish

DOI: 10.3233/JAD-210128

Citation: Journal of Alzheimer's Disease, vol. 82, no. 1, pp. 327-347, 2021

Authors: Hin, Nhi | Newman, Morgan | Pederson, Stephen | Lardelli, Michael

Article Type: Research Article

Abstract: Background: Iron trafficking and accumulation is associated with Alzheimer’s disease (AD) pathogenesis. However, the role of iron dyshomeostasis in early disease stages is uncertain. Currently, gene expression changes indicative of iron dyshomeostasis are not well characterized, making it difficult to explore these in existing datasets. Objective: To identify sets of genes predicted to contain iron responsive elements (IREs) and use these to explore possible iron dyshomeostasis-associated gene expression responses in AD. Methods: Comprehensive sets of genes containing predicted IRE or IRE-like motifs in their 3′ or 5′ untranslated regions (UTRs) were identified in human, mouse, and zebrafish reference transcriptomes. Further …analyses focusing on these genes were applied to a range of cultured cell, human, mouse, and zebrafish gene expression datasets. Results: IRE gene sets are sufficiently sensitive to distinguish not only between iron overload and deficiency in cultured cells, but also between AD and other pathological brain conditions. Notably, changes in IRE transcript abundance are among the earliest observable changes in zebrafish familial AD (fAD)-like brains, preceding other AD-typical pathologies such as inflammatory changes. Unexpectedly, while some IREs in the 3′ untranslated regions of transcripts show significantly increased stability under iron deficiency in line with current assumptions, many such transcripts instead display decreased stability, indicating that this is not a generalizable paradigm. Conclusion: Our results reveal IRE gene expression changes as early markers of the pathogenic process in fAD and are consistent with iron dyshomeostasis as an important driver of this disease. Our work demonstrates how differences in the stability of IRE-containing transcripts can be used to explore and compare iron dyshomeostasis-associated gene expression responses across different species, tissues, and conditions. Show more

Keywords: Alzheimer’s disease, computational biology, familial Alzheimer’s disease, gene expression, iron homeostasis, iron responsive element, transcriptomics

DOI: 10.3233/JAD-210200

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1597-1630, 2021

Authors: Ebrahimie, Esmaeil | Moussavi Nik, Seyyed Hani | Newman, Morgan | Van Der Hoek, Mark | Lardelli, Michael

Article Type: Research Article

Abstract: Dominant mutations in the PRESENILIN genes PSEN1 and PSEN2 cause familial Alzheimer’s disease (fAD) that usually shows onset before 65 years of age. In contrast, genetic variation at the PSEN1 and PSEN2 loci does not appear to contribute to risk for the sporadic, late onset form of the disease (sAD), leading to doubts that these genes play a role in the majority of AD cases. However, a truncated isoform of PSEN2 , PS2V, is upregulated in sAD brains and is induced by hypoxia and high cholesterol intake. PS2V can increase γ -secretase activity and suppress the unfolded protein response (UPR), …but detailed analysis of its function has been hindered by lack of a suitable, genetically manipulable animal model since mice and rats lack this PRESENILIN isoform. We recently showed that zebrafish possess an isoform, PS1IV, that is cognate to human PS2V. Using an antisense morpholino oligonucleotide, we can block specifically the induction of PS1IV that normally occurs under hypoxia. Here, we exploit this ability to identify gene regulatory networks that are modulated by PS1IV. When PS1IV is absent under hypoxia-like conditions, we observe changes in expression of genes controlling inflammation (particularly sAD-associated IL1B and CCR5 ), vascular development, the UPR, protein synthesis, calcium homeostasis, catecholamine biosynthesis, TOR signaling, and cell proliferation. Our results imply an important role for PS2V in sAD as a component of a pathological mechanism that includes hypoxia/oxidative stress and support investigation of the role of PS2V in other diseases, including schizophrenia, when these are implicated in the pathology. Show more

Keywords: Gene regulatory networks, neurodegenerative diseases, transcriptome profiling, zebrafish

DOI: 10.3233/JAD-150678

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 581-608, 2016

Authors: Barthelson, Karissa | Pederson, Stephen Martin | Newman, Morgan | Jiang, Haowei | Lardelli, Michael

Article Type: Research Article

Abstract: Background: Mutations in PRESENILIN 2 (PSEN2 ) cause early onset familial Alzheimer’s disease (EOfAD) but their mode of action remains elusive. One consistent observation for all PRESENILIN gene mutations causing EOfAD is that a transcript is produced with a reading frame terminated by the normal stop codon—the “reading frame preservation rule”. Mutations that do not obey this rule do not cause the disease. The reasons for this are debated. Objective: To predict cellular functions affected by heterozygosity for a frameshift, or a reading frame-preserving mutation in zebrafish psen2 using bioinformatic techniques. Methods: A frameshift mutation (psen2N 140fs ) and a …reading frame-preserving (in-frame) mutation (psen2T 141 _ L 142delinsMISLISV ) were previously isolated during genome editing directed at the N140 codon of zebrafish psen2 (equivalent to N141 of human PSEN2 ). We mated a pair of fish heterozygous for each mutation to generate a family of siblings including wild type and heterozygous mutant genotypes. Transcriptomes from young adult (6 months) brains of these genotypes were analyzed. Results: The in-frame mutation uniquely caused subtle, but statistically significant, changes to expression of genes involved in oxidative phosphorylation, long-term potentiation and the cell cycle. The frameshift mutation uniquely affected genes involved in Notch and MAPK signaling, extracellular matrix receptor interactions and focal adhesion. Both mutations affected ribosomal protein gene expression but in opposite directions. Conclusion: A frameshift and an in-frame mutation at the same position in zebrafish psen2 cause discrete effects. Changes in oxidative phosphorylation, long-term potentiation and the cell cycle may promote EOfAD pathogenesis in humans. Show more

Keywords: Alzheimer’s disease, mitochondria, PSEN2, RNA-seq, zebrafish

DOI: 10.3233/ADR-200279

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 395-404, 2021

Authors: Jayne, Tanya | Newman, Morgan | Verdile, Giuseppe | Sutherland, Greg | Münch, Gerald | Musgrave, Ian | Moussavi Nik, Seyyed Hani | Lardelli, Michael

Article Type: Review Article

Abstract: The majority of mutations causing familial Alzheimer’s disease (fAD) have been found in the gene PRESENILIN1 (PSEN1 ) with additional mutations in the related gene PRESENILIN2 (PSEN2 ). The best characterized function of PRESENILIN (PSEN) proteins is in γ-secretase enzyme activity. One substrate of γ-secretase is encoded by the gene AMYLOID BETA A4 PRECURSOR PROTEIN (A βPP/APP ) that is a fAD mutation locus. AβPP is the source of the amyloid-β (Aβ) peptide enriched in the brains of people with fAD or the more common, late onset, sporadic form of AD, sAD. These observations have resulted in a focus on …γ-secretase activity and Aβ as we attempt to understand the molecular basis of AD pathology. In this paper we briefly review some of the history of research on γ-secretase in AD. We then discuss the main ideas regarding the role of γ-secretase and the PSEN genes in this disease. We examine the significance of the “fAD mutation reading frame preservation rule” that applies to PSEN1 and PSEN2 (and A βPP ) and look at alternative roles for AβPP and Aβ in fAD. We present a case for an alternative interpretation of published data on the role of γ-secretase activity and fAD-associated mutations in AD pathology. Evidence supports a “PSEN holoprotein multimer hypothesis” where PSEN fAD mutations generate mutant PSEN holoproteins that multimerize with wild type holoprotein and dominantly interfere with an AD-critical function(s) such as autophagy or secretion of Aβ. Holoprotein multimerization may be required for the endoproteolysis that activates PSENs’ γ-secretase activity. Show more

Keywords: Amyloid precursor protein secretases, familial Alzheimer’s disease, gamma-secretase, human APP protein, human PSEN1 protein, human PSEN2 protein

DOI: 10.3233/JAD-151186

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 781-799, 2016

Authors: Moussavi Nik, Seyyed Hani | Wilson, Lachlan | Newman, Morgan | Croft, Kevin | Mori, Trevor A. | Musgrave, Ian | Lardelli, Michael

Article Type: Research Article

Abstract: Oxygen homeostasis is essential for the development and normal physiology of an organism. Hypoxia causes the mitochondrial electron transport chain to generate higher levels of reactive oxygen species resulting in oxidative stress. Hypoxia can be a direct consequence of hypoperfusion, a common vascular component among Alzheimer's disease (AD) risk factors, and may play an important role in AD pathogenesis. Beta-site amyloid-β A4 precursor protein-cleaving enzyme 1 (BACE1) is responsible, with γ-secretase, for cleavage of the amyloid-β protein precursor (AβPP) to produce amyloid-β (Aβ) peptide. A recent study observed that oxidative stress increases BACE1 expression via a regulatory pathway dependent on …γ-secretase cleavage of AβPP and this increases Aβ peptide production. Zebrafish embryos represent normal cells in which complex and subtle manipulations of gene activity can be performed to facilitate analysis of genes involved in human disease. Here we identify and describe the expression of bace1, the zebrafish ortholog of human BACE1. We observe that the zebrafish AD-related genes bace1, psen1, psen2, appa, and appb all show increased mRNA levels under hypoxia. A dominant negative form of psen1 putatively blocking γ-secretase activity blocks bace1 upregulation under hypoxia. Hypoxia increases catalase gene mRNA indicating increased oxidative stress but we did not observe increased levels of F2-isoprostanes that indicate peroxidation of arachidonic acid, possibly due to relatively low levels of arachidonic acid in zebrafish. Our results demonstrate that upregulation of PSEN1 & 2, AβPP and the γ-secretase-dependent upregulation of BACE1 is an ancient, conserved, and thus selectively advantageous response to hypoxia/oxidative stress. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, BACE1, hypoxia, oxidative stress, presenilins, γ-secretase, zebrafish

DOI: 10.3233/JAD-2011-110533

Citation: Journal of Alzheimer's Disease, vol. 28, no. 3, pp. 515-530, 2012