Abstract
Amyloid β (Aβ) in brain parenchyma is thought to play a central role in the pathogenesis of Alzheimer's disease (AD). Aβ is transported from the brain to the plasma via complex transport mechanisms at the blood-brain barrier (BBB). About 90–95% of plasma Aβ may be bound to albumin. Replacement of serum albumin in plasma has been proposed as a promising therapy for AD. However, the efficacy of this approach may be compromised by altered BBB Aβ receptors in AD, as well as multiple pools of Aβ from other organs in exchange with plasma Aβ, competing for albumin binding sites. The flow of interstitial fluid (ISF) into cerebrospinal fluid (CSF) is another major route of Aβ clearance. Though the concentration of albumin in CSF is much lower than in plasma, the mixing of CSF with ISF is not impeded by a highly selective barrier and, hence, Aβ in the two pools is in more direct exchange. Furthermore, unlike in plasma, Aβ in CSF is not in direct exchange with multiple organ sources of Aβ. Here we consider albumin replacement in CSF as an alternative method for therapeutic brain Aβ removal and describe the possible advantages and rationale supporting this hypothesis.
Highlights
Aggregation of amyloid-β (Aβ) in the brain parenchyma and arterial walls and the formation of neurofibrillary tangles in neurons due to phosphorylated tau protein accumulation are the main histologic hallmarks of Alzheimer’s disease (AD)
Could cerebrospinal fluid (CSF) exchange be more efficacious than plasma exchange for the replacement of albumin to treat AD? We summarize three points from the discussion above that support the hypothesis that it could be: 1) The origin of CSF Aβ is mostly cerebral, whereas the origin of plasma Aβ is from the entire body, with just a small proportion coming from the brain
2) If soluble cleavage product of LRP1 (sLRP) is the principal carrier of brain-derived Aβ as some studies suggest [15], plasma albumin replacement may have only a minor effect on brain-derived Aβ, since the sLRP carrier is released from the luminal side of the blood–brain barrier (BBB) after lipoprotein receptor-related protein-1 (LRP1)-Aβ transcytosis and is hypothetically already tightly bound to Aβ
Summary
Aggregation of amyloid-β (Aβ) in the brain parenchyma and arterial walls and the formation of neurofibrillary tangles in neurons due to phosphorylated tau protein accumulation are the main histologic hallmarks of Alzheimer’s disease (AD). In an ongoing clinical trial [34], the safety and efficacy of using plasma exchange to remove albumin-bound Aβ for treating AD is being explored [35,36,37]. The concept behind this approach is that a reduction of the albumin-bound Aβ pool in plasma will, in turn, reduce Aβ levels in the parenchyma of the brain, known as the “peripheral sink” hypothesis [38,39,40]. In addition to plasma exchange, adding synthetic albumin to CSF has been explored as a more direct route to augmenting the capture and elimination of toxic forms of interstitial brain Aβ. The positive findings of Ezra et al on direct infusion of albumin into CSF along with the potential limitations of plasma exchange motivate us to propose an approach that combines aspects of both: CSF exchange with albumin replacement
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