Article ; Online: Presenilin-1 Targeted Morpholino Induces Cognitive Deficits, Increased Brain Aβ
2017 Volume 42, Issue 10, Page(s) 2959–2967
Abstract: Presenilins are transmembrane proteases required for the proteolytic cleavage of Notch and also act as the catalytic core of the γ-secretase complex, which is responsible for the final cleavage of the amyloid precursor protein into Amyloid-β (Aβ) ... ...
| Abstract | Presenilins are transmembrane proteases required for the proteolytic cleavage of Notch and also act as the catalytic core of the γ-secretase complex, which is responsible for the final cleavage of the amyloid precursor protein into Amyloid-β (Aβ) peptides of varying lengths. Presenilin-1 gene (psen1) mutations are the main cause of early-onset autosomal-dominant Familial Alzheimer Disease. Elucidating the roles of Presenilin-1 and other hallmark proteins involved in Alzheimer's disease is crucial for understanding the disease etiology and underlying molecular mechanisms. In our study, we used a morpholino antisense nucleotide that targets exon 8 splicing site of psen1 resulting in a dominant negative protein previously validated to investigate behavioral and molecular effects in 5 days post fertilization (dpf) zebrafish larvae. Morphants showed specific cognitive deficits in two optomotor tasks and morphological phenotypes similar to those induced by suppression of Notch signaling pathway. They also had increased mRNA levels of neurog1 at 5 dpf, confirming the potential interaction of Presenilin-1 and Notch in our model. We also evaluated levels of apoptotic markers including p53, PAR-4, Caspase-8 and bax-alpha and found only bax-a decreased at 5dpf. Western Blot analysis showed an increase in Aβ |
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| MeSH term(s) | Alzheimer Disease/metabolism ; Amyloid beta-Peptides/genetics ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/genetics ; Animals ; Brain/metabolism ; Cognition/physiology ; Cognitive Dysfunction/genetics ; Cognitive Dysfunction/metabolism ; Disks Large Homolog 4 Protein/metabolism ; Larva ; Morpholinos/metabolism ; Mutation/genetics ; Peptide Fragments/genetics ; Peptide Fragments/metabolism ; Presenilin-1/metabolism ; Synapses/metabolism ; Zebrafish ; Zebrafish Proteins/genetics ; Zebrafish Proteins/metabolism |
| Chemical Substances | Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Disks Large Homolog 4 Protein ; Morpholinos ; Peptide Fragments ; Presenilin-1 ; Psen1 protein, zebrafish ; Zebrafish Proteins ; amyloid beta-protein (1-42) |
| Language | English |
| Publishing date | 2017-06-16 |
| Publishing country | United States |
| Document type | Journal Article |
| ZDB-ID | 199335-5 |
| ISSN | 1573-6903 ; 0364-3190 |
| ISSN (online) | 1573-6903 |
| ISSN | 0364-3190 |
| DOI | 10.1007/s11064-017-2327-4 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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