Research Statement:

The Ho-Beffert Lab, led by Dr. Angela Ho and in close collaboration with Dr. Beffert, is dedicated to advancing the understanding of neurological diseases through active genetics and genomics research. Our work has significantly contributed to identifying the role of alternative splicing in Alzheimer's disease (AD) and exploring its functional implications on neuronal receptors.

Key Research Highlights:

1. Alternative Splicing in Alzheimer's Disease: Our recent study involved transcriptomic profiling of aged human postmortem brain samples, uncovering aberrant mRNA splicing events associated with AD. We focused on the apolipoprotein E receptor 2 (APOER2), a receptor interacting with the neuroprotective ligand Reelin and the AD-associated risk factor APOE. Utilizing single-molecule, long-read sequencing, we profiled the entire APOER2 transcript from the parietal cortex and hippocampus of Braak stage IV AD brain tissues along with age-matched controls. Our analysis revealed diverse patterns of cassette exon skipping in APOER2 isoforms, some region-specific or unique to AD-affected brains. Notably, exon 15 of APOER2, encoding the glycosylation domain, showed reduced inclusion in AD brains compared to controls, particularly in the parietal cortex of females with the APOE ?3/?3 genotype. These splicing variations were linked to changes in cell surface expression, APOE-mediated receptor processing, and synaptic number, suggesting a critical role in inducing synaptic alterations and contributing to neuronal dysfunction in AD.

2. Conservation and Divergence of Alternative Splicing Across Species: In another study, we investigated the alternative splicing of Apoer2 across vertebrate species, identifying conserved and divergent splicing events that contribute to functional diversity in the brain. Using single-molecule, long-read RNA sequencing, we profiled full-length Apoer2 isoforms and identified 68 unique isoforms in mice and 48 in humans. We discovered species-specific splicing decisions, such as the tandem skipping of exons encoding protein functional domains in mice, providing new insights into the regulatory mechanisms driving Apoer2 isoform complexity and its functional implications.