Abstract
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.
Highlights
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)
We conclude that interventions based in a “CSF-sink” of Aβ will probably produce a steady clearance of Aβ in the ISF and it may represent a new therapeutic strategy in AD
Amyloid beta (Aβ) denotes peptides of 36–43 amino acids that are intrinsically unstructured, meaning that in solution it does not acquire a unique tertiary fold but rather populates a set of structures. These peptides derive from the amyloid precursor protein (APP), which is cleaved by beta- (BACE) and gamma-secretases to yield Aβ (Menendez-Gonzalez et al, 2005; O’Nuallain et al, 2010)
Summary
Amyloid beta (Aβ) denotes peptides of 36–43 amino acids that are intrinsically unstructured, meaning that in solution it does not acquire a unique tertiary fold but rather populates a set of structures. Results from cross-sectional analysis in familial AD demonstrate higher levels of Aβ in the CSF from mutation carriers compared to controls very early in the disease process (∼20–30 years prior to estimated symptom onset), which drop with disease progression, becoming significantly lower than controls ∼10–20 years prior to symptom onset (Morrone et al, 2015; Tarasoff-Conway et al, 2015). These low levels begin to plateau with the development of cognitive symptoms (Iliff et al, 2013). In sporadic AD at very early preclinical stage (transitional stage) there might be either elevations or reductions in CSF AP42 (Clark et al, 2018; de Leon et al, 2018)
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