Relevance of a Truncated PRESENILIN 2 Transcript to Alzheimer's Disease and Neurodegeneration.

Background: The PRESENILIN genes (PSEN1, PSEN2) encoding for their respective proteins have critical roles in many aspects of Alzheimer's disease (AD) pathogenesis. The PS2V transcript of PSEN2 encodes a truncated protein and is upregulated in AD brains; however, its relevance to AD and disease progression remains to be determined.

Objective: Assess transcript levels in postmortem AD and non-AD brain tissue and in lymphocytes collected under the Australian Imaging Biomarker and Lifestyle (AIBL) study.

Gene Ontology-Based Analysis of Zebrafish Omics Data Using the Web Tool Comparative Gene Ontology.

Gene Ontology (GO) analysis is a powerful tool in systems biology, which uses a defined nomenclature to annotate genes/proteins within three categories: "Molecular Function," "Biological Process," and "Cellular Component." GO analysis can assist in revealing functional mechanisms underlying observed patterns in transcriptomic, genomic, and proteomic data. The already extensive and increasing use of zebrafish for modeling genetic and other diseases highlights the need to develop a GO analytical tool for this organism.

Evidence For and Against a Pathogenic Role of Reduced γ-Secretase Activity in Familial Alzheimer's Disease.

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 (AβPP/APP) that is a fAD mutation locus.

The Zebrafish Equivalent of Alzheimer's Disease-Associated PRESENILIN Isoform PS2V Regulates Inflammatory and Other Responses to Hypoxic Stress.

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.

Analysis of nicastrin gene phylogeny and expression in zebrafish.

NICASTRIN is a component of the aspartyl protease γ-secretase complex which is involved in intramembranous cleavage of type I transmembrane proteins, notably the Notch receptor proteins and the AMYLOID BETA A4 PRECURSOR PROTEIN (APP). This study aimed to characterize the orthologue of the human NICASTRIN (NCSTN) gene in zebrafish, an advantageous model organism for the study of human disease. Zebrafish Nicastrin protein was predicted to possess the conserved glutamate 333 residue and DYIGS motif of human NCSTN that are important for substrate recognition/processing in γ-secretase.

Alzheimer's disease-related peptide PS2V plays ancient, conserved roles in suppression of the unfolded protein response under hypoxia and stimulation of γ-secretase activity.

The PRESENILIN1 and PRESENILIN2 genes encode structurally related proteases essential for γ-secretase activity. Of nearly 200 PRESENILIN mutations causing early onset, familial Alzheimer's disease (FAD) only the K115Efx10 mutation of PSEN2 causes truncation of the open reading frame. If translated, the truncated product would resemble a naturally occurring isoform of PSEN2 named PS2V that is induced by hypoxia and found at elevated levels in late onset Alzheimer's disease (AD) brains.

Hypoxia alters expression of zebrafish microtubule-associated protein tau (mapta, maptb) gene transcripts.

Background: Microtubule-associated protein tau (MAPT) is abundant in neurons and functions in assembly and stabilization of microtubules to maintain cytoskeletal structure. Human MAPT transcripts undergo alternative splicing to produce 3R and 4R isoforms normally present at approximately equal levels in the adult brain. Imbalance of the 3R-4R isoform ratio can affect microtubule binding and assembly and may promote tau hyperphosphorylation and neurofibrillary tangle formation as seen in neurodegenerative diseases such as frontotemporal dementia (FTD) and Alzheimer's disease (AD).

Identification and expression analysis of the zebrafish orthologues of the mammalian MAP1LC3 gene family.

Autophagy is the principle pathway within cells involved in clearing damaged proteins and organelles. Therefore autophagy is necessary to maintain the turnover balance of peptides and homoeostasis. Autophagy occurs at basal levels under normal conditions but can be upregulated by chemical inducers or stress conditions.

The comparison of methods for measuring oxidative stress in zebrafish brains.

The zebrafish is a versatile model organism with the potential to contribute to our understanding of the molecular pathological mechanisms underlying Alzheimer's disease (AD). An early characteristic of AD brain pathology is lipid peroxidation resulting from oxidative stress. However, changes in lipid peroxidation have not yet been assessed in zebrafish brains, and an earlier attempt to observe changes in F₂-isoprostane levels in the brains of zebrafish exposed to hypoxia was unsuccessful.

Differential, dominant activation and inhibition of Notch signalling and APP cleavage by truncations of PSEN1 in human disease.

PRESENILIN1 (PSEN1) is the major locus for mutations causing familial Alzheimer's disease (FAD) and is also mutated in Pick disease of brain, familial acne inversa and dilated cardiomyopathy. It is a critical facilitator of Notch signalling and many other signalling pathways and protein cleavage events including production of the Amyloidβ (Aβ) peptide from the AMYLOID BETA A4 PRECURSOR PROTEIN (APP). We previously reported that interference with splicing of transcripts of the zebrafish orthologue of PSEN1 creates dominant negative effects on Notch signalling.

The BACE1-PSEN-AβPP regulatory axis has an ancient role in response to low oxygen/oxidative stress.

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.

The response of HMGA1 to changes in oxygen availability is evolutionarily conserved.

Zebrafish embryos have evolved to cope with hypoxia during development. This includes the ability to completely suspend embryo development for extended periods until normoxia is restored. However, only a limited number of studies have examined the gene regulatory responses of zebrafish embryos to hypoxia.