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Front Aging Neurosci. 2018 Apr 16;10:100. doi: 10.3389/fnagi.2018.00100. eCollection 2018.

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

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Servicio de Neurologia, Hospital Universitario Central de Asturias, Oviedo, Spain.
Department of Cellular Morphology and Biology, University of Oviedo, Oviedo, Spain.
Instituto de Investigacion Sanitaria del Principado de Asturias, Oviedo, Spain.
Centro de Investigaciones Biomedicas (CIB), University of Cartagena, Cartagena, Colombia.
HealthSens, S.L., Oviedo, Spain.
Departamento de Neurociencias, Universidad del Pais Vasco (UPV/EHU), Leioa, Spain.
El Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain.
Achucarro Basque Center for Neuroscience, Leioa, Spain.
Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
Department of Functional Biology, University of Oviedo, Oviedo, Spain.
Department of Physical and Analytical Chemistry, University of Oviedo, Oviedo, Spain.


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


Alzheimer disease; amyloid beta-peptides; cerebrospinal fluid; immunotherapy; “CSF sink hypothesis”

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