Presenilin-1 Targeted Morpholino Induces Cognitive Deficits, Increased Brain Aβ_1-42 and Decreased Synaptic Marker...

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_1-42 and a decrease in the selective post-synaptic marker PSD-95 at 5 dpf. Our data demonstrates that psen1 splicing interference induces phenotypes that resemble early-stage AD, including cognitive deficit, Aβ_1-42 accumulation and synaptic reduction, reinforcing the potential contribution of zebrafish larvae to studies of human brain diseases.