ApoE4, the most significant genetic risk factor for late-onset Alzheimer’s disease (AD), sequesters a pro-synaptogenic receptor, Apoer2, which protects against amyloid-β (Aβ) toxicity. Apoer2 plays a critical role in synaptic function, a process regulated by alternative splicing of the receptor. Moreover, Apoer2 processing releases an ICD capable of regulating transcription and its splicing can ameliorate behavioral deficits in an AD mouse model. However, the role of this splicing in transcriptional regulation is unknown. Here, we assessed in vivo changes in ribosome-associated hippocampal transcripts after lentiviral delivery of Apoer2-ICD splice variants in wild-type, cKO, and Apoer2 cleavage-resistant mice. Across all conditions, we observed altered ribosome-associated transcripts of key synaptic components regulating the extracellular matrix and focal adhesions with concomitant perturbation of critical signaling cascades, energy metabolism, translation, and apoptosis. These are common signatures observed in neuropathological disorders, suggesting Apoer2 holds a potential key for unlocking future therapeutic interventions across the spectrum of neurological disorders.
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Sep 22, 2023
Wasser, Catherine, 2023, "Luciferase Data - related to Figure S1", https://doi.org/10.18738/T8/LARZLE, Texas Data Repository, V1
Figure S1: Regulation of Apoer2-ICD promoter-binding and effects of Apoer2-ICD mutations on Reln-promoter binding in vitro.
Sep 22, 2023
Wasser, Catherine, 2023, "RNA-sequencing analysis files", https://doi.org/10.18738/T8/WPUGXX, Texas Data Repository, V1, UNF:6:DpLgsuMv9Y1bvOq7eo7Ylg== [fileUNF]
Analysis files related to figures 1-8
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