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Low-density lipoprotein receptor-related protein 5 (LRP5) is a constitutively expressed receptor with observed roles in bone homeostasis, retinal development, and cardiac metabolism. However, the function of LRP5 in the brain remains unexplored. This study investigates LRP5’s role in the central nervous system by conducting an extensive analysis using RNA-seq tools and in silico assessments. Two protein-coding <i>Lrp5</i> transcripts are expressed in mice: full-length <i>Lrp5-201</i> and a truncated form encoded by <i>Lrp5-202</i>. <i>Wt</i> mice express <i>Lrp5-201</i> in the liver and brain and do not express the truncated form. <i>Lrp5</i>^−/− mice express <i>Lrp5-202</i> in the liver and brain and do not express <i>Lrp5-201</i> in the liver. Interestingly, <i>Lrp5</i>^−/− mouse brains show full-length <i>Lrp5-201</i> expression, suggesting that <i>LRP5</i> has a role in preserving brain function during development. Functional gene enrichment analysis on RNA-seq unveils dysregulated expression of genes associated with neuronal differentiation and synapse formation in the brains of <i>Lrp5</i>^−/− mice compared to <i>Wt</i> mice. Furthermore, Gene Set Enrichment Analysis highlights downregulated expression of genes involved in retinol and linoleic acid metabolism in <i>Lrp5</i>^−/− mouse brains. Tissue-specific alternative splicing of <i>Lrp5</i> in <i>Lrp5</i>^−/− mice supports that the expression of <i>LRP5</i> in the brain is needed for the correct synthesis of vitamins and fatty acids, and it is indispensable for correct brain development.