Edited by: Mohammad Amjad Kamal, King Abdulaziz University, Saudi Arabia
Reviewed by: Fabrizio Piazza, Università degli Studi di Milano Bicocca, Italy; Alessandro Stefani, Università degli Studi di Roma Tor Vergata, Italy
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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.
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 (
Amyloid beta is cleared from the brain by several independent mechanisms (
The pathophysiology of Alzheimer’s disease (AD) is characterized by the accumulation of Aβ and phospho-tau protein in the form of neuritic plaques and neurofibrillary tangles, respectively (
Amyloid-β accumulation has been hypothesized to result from an imbalance between Aβ production and clearance. An overproduction is probably the main cause of the disease in the familial AD where a mutation in the
The different clearance systems probably contribute to varying extents on Aβ homeostasis. Any alteration to their function may trigger the progressive accumulation of Aβ (
Different approaches have been investigated with the aim of removing brain Aβ. Decreasing Aβ production might be the first approach that one can think of to reduce ISF Aβ. For instance, the inhibition BACE is one of the first therapeutic strategies formulated after the amyloid cascade hypothesis, and it is still being explored today. Alternatively, increasing the elimination of Aβ by enzymatic degradation or by clearance enhancement may be able to slow down both the aggregation and the spread processes of the disease given the relevance of Aβ as a substrate in AD (
The Aβ immunotherapy consist on activating the immune system against Aβ through the induction (active immunotherapy) or administration (passive immunotherapy) of Aβ-antibodies (
Some interventions have been shown to produce some positive changes on brain Aβ, both in animal models and in human subjects. Unfortunately, these neuropathological benefits were not accompanied by sufficient clinical benefit; therefore, none of these therapies have been transferred to the clinic. One of the reasons may be that effective development of AD therapeutic strategies targeting Aβ require very early administration (before amyloid-plaques are in place) and consideration of the age- and ApoE-specific changes to endogenous Aβ clearance mechanisms in order to optimize efficacy (
Understanding how Aβ-antibodies remove Aβ from the brain is a key in the design of Aβ immunotherapies for AD. Two distinct but not mutually exclusive mechanisms have been proposed: The “microglial phagocytosis” would require the antibodies to enter the brain, where they mediate the uptake of Aβ into local microglia. The “peripheral sink” mechanism of action relies only on peripheral antibodies to sequester Aβ in the systemic blood, lowering the level of free Aβ and inducing the brain to release its store of the peptide. This sequestration of circulating Aβ produces a shift in the concentration gradient of Aβ between the brain and the blood causing an efflux of Aβ out of the brain. Thus, it has been hypothesized that reducing Aβ peptides in the periphery would be a way to diminish Aβ levels and plaque load in the brain (
On the other hand, sustained peripheral depletion of Aβ with a new form of neprilysin, which fuses with albumin to prolong plasma half-life, is designed to confer increased Aβ degradation activity and does not affect central Aβ levels in transgenic mice, rats and monkeys (
Administered monoclonal antibodies also showed molecular effect, but clinical benefit in humans was not significant. For instance, Solanezumab increases the elimination of soluble Aβ and decreases the deposition of cerebral amyloid plaque in AD mice. In clinical trials, the administration of Solanezumab in patients with mild to moderate AD generated an increase of unbound Aβ in CSF, suggesting that the antibody has a direct peripheral effect with central indirect effect. However, clinical trials showed not improvement of the cognitive and functional capacities of patients (
Many investigators have indicated that peripheral clearance through the BBB is not recommended in elderly people, in whom the normal transport of Aβ may present alterations. In addition, the risk of antibody-mediated hemorrhage in sites of cerebral amyloid angiopathy decreases the authors’ interest in peripheral passive as well as in active reduction mediated by CNS Aβ antibodies. Due to this, it has been considered that the direct administration of immunotherapy to the CNS is more efficient than the peripheral one, but the intrinsic characteristics of the BBB make the pharmacological approach difficult. This has led to the search for strategies to overcome the BBB. These approaches were divided into two categories: the first comprises techniques that facilitate the passage of drugs through the BBB (for example, molecular “Trojan horses,” oligopeptides transporters coupled to protons, exosomes, liposomes, nanoparticles, chimeric peptides, prodrugs); and the second consists on techniques that avoid BBB through direct delivery to the SNC. In this last category, the techniques have been investigated include the interruption of BBB (for example, with ultrasound and microbubbles) and intrathecal, intracerebroventricular and intranasal administration (
Some human monoclonal antibodies have been shown to enter the brain even when administered peripherally. In a transgenic mouse model of AD, Aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, 1 year of monthly intravenous infusions of Aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline. The main safety issues are amyloid-related imaging abnormalities (
In conclusion, no Aβ immunotherapy has demonstrated significant efficacy in humans to date. A meta-analysis of immunotherapies (
Despite Aβ immunotherapy showed not conclusive results to date, Aβ remains the main target in AD. A study using an image biomarker determined that a 15% decrease in Aβ is related to a cognitive improvement of 15–20% (
A number of studies showed that blood dialysis and plasmapheresis reduces Aβ levels in plasma and CSF in humans and attenuates AD symptoms and pathology in AD mouse models (58,6165), suggesting that removing Aβ from the plasma seems to be an effective -albeit indirect- way of removing Aβ. Different methodologies, from peritoneal dialysis (
Double dynamic equilibrium of Aβ: there is a bidirectional equilibrium between insoluble and soluble pools of Aβ in the ISF and there is a second equilibrium, also probably bidirectional, of soluble Aβ between the ISF and the CSF. The “CSF-sink therapeutic strategy” consists on sequestering target proteins from the CSF with implantable devices, thus inducing changes in the levels of these proteins in the ISF. Current therapeutic strategies rely on the “peripheral sink” hypothesis mostly. There is some controversy about the existence of a equilibrium of Aβ between plasma and the ISF/CSF.
However, there might be a much more direct way of removing Aβ from the ISF than clearing it from the plasma: clearing it from the CSF. A starting rationale is that there is an equilibrium of Aβ levels between the ISF and plasma in AD transgenic mice before developing Aβ deposits (
We previously posed the hypothesis that soluble proteins can be cleared from the brain with interventions where soluble proteins are continuously removed from the CSF (
Diagram representing the therapeutic effect of a “CSF-sink” intervention on the predicted levels of Aβ in the insoluble ISF (isISF), soluble ISF (sISF) and CSF pools in a patient with AD treated at presymptomatic stage. Legend: +, positive deposits; -, negative deposits; N, normal; H, high; VH, very high; L, low; VL, very low.
The “CSF-sink” therapeutic strategy consists on sequestering Aβ from the CSF (
A study on the Aβ clearance kinetics suggests that the speed and efficiency of Aβ clearance pathways may influence the effect on Aβ deposits (
Graph representing the evolution of Aβ in the different pools. On the left, evolution of Aβ levels across the different stages of a AD. On the right, predicted evolution of Aβ levels in a case of AD treated at presymptomatic stage. islSF, insoluble pool in the ISF; slSF, soluble pool in the ISF.
Albeit AD is a complex disease, and targeting one single molecule might not be enough to hinder the whole neurodegenerative process, we consider this strategy is worth trying, since it is feasible and potentially efficient.
Finally, we would like to mention this strategy might also be valid for other neurodegenerative and neuroimmune diseases where target molecules are well identified and present in the CSF in equilibrium with the ISF. A series of studies in cellular and animal models are needed to prove this hypothesis.
We introduce the rationale basis for the “CSF-sink” hypothesis and conclude that continuous depletion of Aβ in the CSF will probably produce a steady clearance of Aβ in the ISF. Implantable devices aimed at sequestering Aβ from the CSF may represent a new therapeutic strategy in AD.
MM-G is the author of the hypothesis and wrote the whole manuscript. All the other authors revised the existing literature and critically reviewed the manuscript.
GA is employed by HealthSens, S.L. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.