Preprint: A brain-persistent DDR2-degrading antibody reverses Alzheimer's pathologies by restoring brain fluid dynamics and metabolic clearance

WHY IT MATTERS

This research identifies a new therapeutic target for Alzheimer's disease that works through a different mechanism than current treatments, potentially offering hope for patients whose disease progresses despite existing amyloid-targeting therapies.

Researchers found that a protein called DDR2 is overactive in Alzheimer's disease and may be blocking the brain's natural cleaning system. They developed an antibody (a type of immune protein) that can cross into the brain and reduce DDR2 levels, which in early studies helped restore the brain's ability to clear out harmful waste products and improved Alzheimer's symptoms in animal models.

A brain-persistent DDR2-degrading antibody reverses Alzheimer's pathologies by restoring brain fluid dynamics and metabolic clearance Authors: Yang, P. et al. Server: medRxiv Category: neurology Abstract: Alzheimers disease (AD) is defined by A{beta} deposition, yet cerebrovascular and glymphatic dysfunction are early drivers of progression. We identify discoidin domain receptor 2 (DDR2), a collagen-sensing receptor tyrosine kinase, as a central mediator of neurovascular impairment in AD. Integrative analysis of human single-nucleus RNA (snRNA)-seq data and immunohistochemical validation across human, non-human primate, and mouse AD models revealed that DDR2 is markedly upregulated in reactive astrocytes, perivascular fibroblasts (PVFs), and choroid plexus epithelial cells (CPECs). Astrocytic D