Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Familial Alzheimer's disease (AD) is linked to pathogenic variants in PSEN1 and PSEN2.
• Sporadic AD shows differential regulation of PSEN2 3' untranslated region (3'UTR) isoforms, including short and extended forms.

Purpose of the Study:

• To investigate the functional significance of PSEN2 3'UTR isoforms in Alzheimer's disease.
• To establish in vitro models for assessing PSEN2 3'UTR isoform regulation.
• To profile miRNA expression in AD and control brain samples.

Main Methods:

• Developed in vitro models using HMC3 and SH-SY5Y cell lines with PSEN2 3'UTR constructs.
• Performed small RNA sequencing on AD and control homogenate and synaptosome fractions.
• Utilized BaseScope in-situ hybridization to analyze PSEN2 3'UTR isoform localization in human frontal cortex.

Main Results:

• Short PSEN2 was predominantly cytoplasmic and decreased in AD frontal cortex; long PSEN2 was nuclear with similar levels in AD and controls.
• Identified differentially regulated miRNAs in AD brain fractions, including miR-34c.
• The long PSEN2 3'UTR contains binding sites for several differentially regulated miRNAs implicated in AD.

Conclusions:

• Established an in vitro model for PSEN2 3'UTR isoform studies.
• Characterized miRNA expression differences in human AD brain fractions.
• Observed decreased PSEN2 transcript signal in human AD frontal cortex, highlighting the importance of 3'UTR isoform regulation in AD pathogenesis.