Clearing amyloid β from the brain

Abstract

In the brain, arteries and veins do not run in parallel, and its perfusion system has characteristics not found in other organs. The presence of a tight blood–brain barrier and lack of authentic lymphatic vessels in the parenchyma means clearance of some waste products, such as amyloid β (Aβ), is impeded. Aβ is thus cleared from the brain via at least four clearance pathways including 1) transcytotic delivery, 2) intramural periarterial drainage, 3) glymphatic drainage and 4) enzymatic or glial degradation. Failure in any four such pathways has been implicated in the pathophysiological processes behind Alzheimer disease. In clinical trials of Aβ vaccination therapy, vascular Aβ deposition was paradoxically enhanced, with encephalitis subsequently occurring in a fraction of patients. This serious side effect may be associated with insufficient clearance of solubilized Aβ through clearance systems in response to immunotherapy. Transcytotic delivery, intramural periarterial drainage, and glymphatic drainage clearance pathways depend on vascular integrity and are partly driven by vascular wall motion; therefore arteriosclerosis or perfusion pressure reduction is assumed to increase Aβ accumulation. Strategies activating clearance systems may be helpful in the treatment of intractable disease through reduction of brain Aβ, therefore aiding development of neurovascular prevention strategies for Alzheimer disease.