Advances in Amyloid-β Clearance in the Brain and Periphery: Implications for Neurodegenerative Diseases

This review examines the role of impaired amyloid-beta clearance in the accumulation of amyloid-beta in the brain and the periphery, which is closely associated with Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). The molecular mechanism underlying amyloid-beta accumulation is largely unknown, but recent evidence suggests that impaired amyloid-beta clearance plays a critical role in its accumulation. The review provides an overview of recent research and proposes strategies for efficient amyloid-beta clearance in both the brain and periphery. The clearance of amyloid-beta can occur through enzymatic or non-enzymatic pathways in the brain, including neuronal and glial cells, blood-brain barrier, interstitial fluid bulk flow, perivascular drainage, and cerebrospinal fluid absorption-mediated pathways. In the periphery, various mechanisms, including peripheral organs, immunomodulation/immune cells, enzymes, amyloid-beta-binding proteins, and amyloid-beta-binding cells, are involved in amyloid-beta clearance. Although recent findings have shed light on amyloid-beta clearance in both regions, opportunities remain in areas where limited data is available. Therefore, future strategies that enhance amyloid-beta clearance in the brain and/or periphery, either through central or peripheral clearance approaches or in combination, are highly encouraged. These strategies will provide new insight into the disease pathogenesis at the molecular level and explore new targets for inhibiting amyloid-beta deposition, which is central to the pathogenesis of sporadic AD (amyloid-beta in parenchyma) and CAA (amyloid-beta in blood vessels).