Whole Blood Exchange and the Peripheral Amyloid Sink Hypothesis
Today I'll point out an interesting study in mice that is based on the peripheral amyloid sink view of Alzheimer's disease. Researchers repeatedly replaced the blood in Alzheimer's model mice, that exhibit high levels of amyloid-β in the brain, with blood from normal mice. The result was less amyloid-β in the brain and better cognitive function. While one does always need to begin these discussions by noting that mouse models of Alzheimer's disease are very artificial constructs, in that mice do not naturally develop the condition, and thus the models are all some form of genetic dysfunction that generates a particular pathology that may or may not map well to why Alzheimer's is harmful in humans, this is nonetheless quite interesting.
The peripheral amyloid sink concept is the suggestion that levels of amyloid-β in the circulation and vascular tissues, on the one hand, and in the brain, on the other hand, are in dynamic equilibrium. If amyloid-β is removed from the vasculature and circulation, such as via replacement of blood, then this will cause amyloid-β levels to drop in the brain. One can consider some form of balance being enacted at the blood-brain barrier, in which the barrier is sensitive to levels of amyloid-β on either side, or more simple diffusion processes. But either way, there is some evidence for this to actually work: a phase III trial in humans was successful in improving cognitive function, using replacement of blood.
However, it is entirely possible that this has absolutely nothing to do with redistribution of amyloid-β, and everything to do with the dilution of harmful factors in the old bloodstream and replacement of circulating age-damaged albumin, rife with modifications due to the age-damaged environment. Blood replacement treatments might be expected to reduce the chronic inflammation and tissue dysfunction that results from the presence of damage-associated molecular patterns and other harmful factors present in the bloodstream of an older individual - and thus perhaps reduction of amyloid-β and restoration of cognitive function has more to do with a modest improvement in the brain tissue environment, allowing greater clearance of amyloid-β by immune cells and less cellular dysfunction in general. Proving this one way or another is quite the different challenge from demonstrating that benefits occur, of course.
Whole blood exchange could offer disease-modifying therapy for Alzheimer's disease, study finds
Researchers have shown that the misfolding, aggregation, and buildup of amyloid beta proteins in the brain plays a central role in Alzheimer's disease. Therefore, preventing and removing misfolded protein aggregates is considered a promising treatment for the disease. After multiple blood transfusions, the researchers found that the development of cerebral amyloid plaques in a transgenic mice model of Alzheimer's disease was reduced by 40% to 80%. This reduction also resulted in improved spatial memory performance in aged mice with the amyloid pathology, and lowered the rates of plaque growth over time.
While the exact mechanism by which this blood exchange reduces amyloid pathology and improves memory is currently unknown, there are multiple possibilities. One possible explanation is that lowering amyloid beta proteins in the bloodstream may help facilitate the redistribution of the peptide from the brain to the periphery. Another theory is that blood exchange somehow prevents amyloid beta influx, or inhibits the re-uptake of cleared amyloid beta, among other potential explanations.
Alzheimer's disease (AD) is the major form of dementia in the elderly population. The main neuropathological changes in AD patients are neuronal death, synaptic alterations, brain inflammation, and the presence of cerebral protein aggregates in the form of amyloid plaques and neurofibrillary tangles. Compelling evidence suggests that the misfolding, aggregation, and cerebral deposition of amyloid-beta (Aβ) plays a central role in the disease. Thus, prevention and removal of misfolded protein aggregates is considered a promising strategy to treat AD.
In the present study, we describe that the development of cerebral amyloid plaques in a transgenic mice model of AD (Tg2576) was significantly reduced by 40-80% through exchanging whole blood with normal blood from wild type mice having the same genetic background. Importantly, such reduction resulted in improvement in spatial memory performance in aged Tg2576 mice. The exact mechanism by which blood exchange reduces amyloid pathology and improves memory is presently unknown, but measurements of Aβ in plasma soon after blood exchange suggest that mobilization of Aβ from the brain to blood may be implicated. Our results suggest that a target for AD therapy may exist in the peripheral circulation, which could open a novel disease-modifying intervention for AD.
could be a way of giving dysfunctional glymphatic system a helping hand
Given that there are numerous indications that AB clearance provides some benefit to AD patients, are there efforts to see what early intervention might do before cognitive decline sets in?
I'd rather have Aducanumab or anything else now in middle age instead of waiting for an ADAS battery 25 years from now to classify me as an AD patient.