Targeting Beta-Amyloid at the CSF: A New Therapeutic Strategy in Alzheimer's Disease

Although immunotherapies against the amyloid-beta (A beta) peptide tried so date failed to prove sufficient clinical benefit, A beta still remains the main target in Alzheimer's disease (AD). This article aims to show the rationale of a new therapeutic strategy: clearing A beta from the CSF continuously (the CSF-sink therapeutic strategy). First, we describe the physiologic mechanisms of A beta clearance and the resulting AD pathology when these mechanisms are altered. Then, we review the experiences with peripheral A beta immunotherapy and discuss the related hypothesis of the mechanism of action of peripheral sink. We also present A beta-immunotherapies acting on the CNS directly. Finally, we introduce alternative methods of removing A beta including the CSF-sink therapeutic strategy. As soluble peptides are in constant equilibrium between the ISF and the CSF, altering the levels of A beta oligomers in the CSF would also alter the levels of such proteins in the brain parenchyma. We conclude that interventions based in a CSF-sink of A beta will probably produce a steady clearance of A beta in the ISF and therefore it may represent a new therapeutic strategy in AD.