The Leucadia Therapeutics team are developing a means to restore the pace at which cerebrospinal fluid drains from the brain. Atrophy of systems of drainage with age causes metabolic wastes such as amyloid and tau to accumulate, leading to Alzheimer's disease. In the past few years, a growing number of papers have emerged in support of this class of approach to the treatment of Alzheimer's. This one is a more general example, suggesting that any means of reducing protein aggregates in cerebrospinal fluid would help - though since a simple fluid flow mechanism already exists in the body, it seems like a good idea to get that working again in older individuals rather than trying something more complex and biochemical, such as immunotherapy.
Amyloid-β (Aβ) is cleared from the brain by several independent mechanisms, including drainage to the vascular and glymphatic systems, and in situ degradation by glial cells. Astrocytes and microglia can produce Aβ degrading proteases like neprilysin, as well as chaperones involved in the clearance of Aβ. There is also a receptor mediated endocytosis, where receptors located in the surface of glial cells are involved in the uptake and clearance of Aβ. In transcytosis, Aβ is removed from interstitial fluid (ISF) across the blood brain barrier (BBB) into the systemic blood.
A perivascular pathway facilitates cerebrospinal fluid (CSF) flow through the brain parenchyma and the clearance of interstitial solutes, including Aβ. It was thought that changes in arterial pulsatility may contribute to accumulation and deposition of toxic solutes, including Aβ, in the aging brain. However, mathematical simulation showed that arterial pulsations are not strong enough to produce drainage velocities comparable to experimental observations and that a valve mechanism such as directional permeability of the intramural periarterial drainage pathway is necessary to achieve a net reverse flow.
The pathophysiology of Alzheimer's disease (AD) is characterized by the accumulation of Aβ and phosphorylated 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 APP, PSEN1, or PSEN2 genes is present while altered clearance is probably the main cause of the disease in sporadic AD. A good amount of studies reporting altered clearance of Aβ in AD have been published in recent years, becoming one of the hot topics in AD research today.
The different clearance systems probably contribute to varying extents on Aβ homeostasis. Any alteration to their function may trigger the progressive accumulation of Aβ, which is the fundamental step in the hypothesis of the amyloid cascade. There is a relationship between the decrease in the rate of turnover of amyloid peptides and the probability of aggregation due to incorrect protein misfolding resulting in its accumulation. As soluble molecules can move in constant equilibrium between the ISF and the CSF, Aβ monomers and oligomers can be detected in the CSF. Indeed, measuring the levels of Aβ in the CSF is one of the main proposed biomarkers already accepted in the diagnostic criteria of AD.
Different approaches have been investigated with the aim of removing brain Aβ. Among all strategies to enhance the clearance of Aβ, immunotherapy is the most explored approach so far, but has failed to show conclusive results to date. There is an urgent need to find alternative methods to achieve a depletion of Aβ in the brain. 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, suggesting that removing Aβ from the plasma seems to be an effective - albeit indirect - way of removing Aβ. 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.
The "CSF-sink" therapeutic strategy consists on sequestering Aβ from the CSF. Today, we can conceive several ways of accessing the CSF with implantable devices. These devices can be endowed with different technologies able to capture target molecules, such as Aβ, from the CSF. Thus, these interventions would work as a central sink of Aβ, reducing the levels of CSF Aβ, and by means of the CSF-ISF equilibrium would promote the efflux of Aβ from the ISF to the CSF. The "CSF-sink" therapeutic strategy is expected to provide an intense and sustained depletion of Aβ in the CSF and, in turn, a steady decrease Aβ in the ISF, preventing the formation of new aggregates and deposits in the short term and potentially reversing the already existing deposits in the medium and long terms.
Link: https://doi.org/10.3...nagi.2018.00100
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