2024/05/08 by Junyang Chen, Pan Xiang, Aroa Duro-Castano +12 · 1 voice
Medicine · Neuroscience · #Alzheimer's disease research and treatments #Axon Guidance and Neuronal Signaling #Neurological Disorders and Treatments
paper · pdf · doi:10.1101/2024.05.06.592767
openalex publication_date 2024/05/08 · openalex created_date 2024/05/09 · openalex updated_date 2026/07/14
Abstract The blood-brain barrier (BBB) is a highly selective permeability barrier that safeguards the central nervous system (CNS) from potentially harmful substances while regulating the transport of essential molecules. Its dysfunction is increasingly recognized as a pivotal factor in the pathogenesis of Alzheimer’s disease (AD), contributing to the accumulation of amyloid-β (Aβ) plaques. We propose an AD therapeutic strategy targeting the BBB low-density lipoprotein receptor-related protein 1 (LRP1). We show that a multivalent scaffold with LRP1-specific peptide modulates the Aβ transport at the BBB. We show via detailed experimentation on AD model mice that this intervention markedly reduces Aβ deposits and prevents cognitive decline. This study marks a new approach to drug design, combining multivalent targeting with the regulation of membrane trafficking through advanced molecular engineering. Crucially, the therapeutic effects emerge from the multivalent nature of our proposed system. Furthermore, our findings underscore the paramount significance of the BBB in AD pathogenesis, particularly emphasizing the critical role of LRP1-mediated Aβ clearance in mitigating disease progression.