川口 和紀

Purpose: Amyloid-β protein (Aβ) is one of the causative proteins of Alzheimer’s disease. We have been developing extracorporeal blood Aβ-removal systems as a method for enhancing Aβ clearance from the brain. We reported previously that medical adsorbents and hemodialyzers removed Aβ monomers from peripheral blood, which was associated with influx of Aβ monomers from the brain into the bloodstream. Our intent here was to develop a method to promote clearance of Aβ oligomers and to provide an estimate of the molecular size of intact Aβ oligomers in plasma. Methods: Two hollow-fiber devices with different pore sizes (Membranes A and B) were evaluated as removers of Aβ oligomers with human plasma in vitro. The concomitant removal of Aβ oligomers and monomers was investigated by using Membrane B and hexadecyl alkylated cellulose beads or polysulfone hemodialyzers. Double-filtration plasma-pheresis with Membrane A was investigated as an approach for the removal of plasma Aβ oligomers in humans. Results: Aβ oligomers were effectively removed by both Membranes A and B. The increase of Aβ oligomers in plasma was observed just after the removal of plasma Aβ oligomers in humans. The intact molecular size of major Aβ oligomers in the plasma was estimated to be larger than albumin at approximately 60 kDa or more. Additionally, the concomitant removal of Aβ monomers and oligomers evoked dissociation of larger Aβ oligomers into smaller ones and monomers. Conclusion: Aβ oligomers were cleared from plasma both in vitro and in human subjects by using hollow-fiber membranes with large pores, indicating that their intact sizes were mostly larger than 60 kDa. Aβ oligomers in peripheral circulation were increased after some clearances in human. Further investigation will determine whether the Aβ oligomers detected in circulation after clearance were via influx from the brain.

Accumulation of amyloid β protein (Aβ) in the brain causes cognitive impairment in Alzheimer's disease (AD). The nature of the relationship between smoking and AD or dementia has been controversial. However, a recent meta-analysis revealed that smoking is a risk factor for AD. With regard to nicotinic acetylcholinergic receptors (nAChRs), both AD and control patients that smoke have been reported to show an increase in 3H-cytisine (an a4β4 nAChR agonist) binding in the temporal cortex. The α7 nAChR is also a key factor in AD pathology, particularly in relation to internalization of Aβs. Furthermore, there are many reports showing the neuroprotective effects of nicotine. The internalization of Aβ may lead to Aβ clearance in the brain. We hypothesized that an extracorporeal system that rapidly removes Aβ from the blood may accelerate Aβ clearance from the brain. We have reported that (1) several medical materials including hemodialyzers can effectively remove blood Aβ, (2) the concentrations of blood Aβs decreased during hemodialysis, (3) removal of blood Aβ enhanced Aβ influx into the blood (ideally from the brain), resulting in maintenance or improvement of cognitive function, and (4) Aβ deposition in the brain of hemodialysis patients was significantly lower than in controls. Smoking affected blood Aβ removal efficiencies and brain atrophy. We believe this Extracorporeal Blood Aβ Removal Systems (E-BARS) may contribute as a therapy for AD.

Background: Chronic kidney disease is a major risk factor for dementia, but the influence of hemodialysis itself on the development of dementia remains unclear. We previously reported that non-diabetic patients on maintenance hemodialysis have preserved cognitive function hemodialysis removes blood amyloid β (Aβ), which is a major cause of Alzheimer's disease in the brain and the number of Aβ deposits in the postmortem brains of hemodialysis patients was significantly less compared to that in age-matched controls not undergoing hemodialysis. We aimed to evaluate the influence of hemodialysis on the development of dementia. Methods: We accessed the Japanese Society for Dialysis Therapy Renal Data Registry between December 31, 2009, and December 31, 2010. Dementia was identified in 120,101 patients undergoing maintenance hemodialysis. The association between hemodialysis duration and dementia risk was analyzed using logistic regression analysis. Results: There was a significant decrease in the dementia risk with an increase in the hemodialysis duration, with odds ratios (95% confidence intervals) of 0.78 (0.74-0.82) and 0.88 (0.78-0.99) for every 10 years in non-diabetic and diabetic patients, respectively. However, in diabetic patients, the correlation between hemodialysis duration and dementia risk was not consistent. Conclusion: A longer hemodialysis duration was correlated with a lower dementia risk, but the correlation between hemodialysis duration and dementia risk in diabetic patients was much weaker and vaguer than that in non-diabetic patients. This finding does not appear to contradict greatly the assumption that the reduction in dementia risk with a prolonged hemodialysis duration in non-diabetic patients was caused not only by the survivor effect but also by hemodialysis itself.