Could Aβ from the blood contribute to Alzheimer’s disease? In the October 31 Molecular Psychiatry, researchers led by Yan-Jiang Wang at Daping Hospital, Third Military Medical University in Chongqing, China, and Weihong Song at the University of British Columbia, Vancouver, Canada, made a case for this. The researchers surgically joined AD model mice to wild-type mice such that the animals shared a blood supply, a technique known as parabiosis. Over several months, circulating human Aβ42 entered the brains of the wild-types. It accumulated there and formed plaques, though it did not appear to seed deposits with endogenous mouse Aβ. Plaque deposition in turn kicked off tau phosphorylation, inflammation, and degeneration.
- Wild-type mice shared a blood supply with AD mice for several months.
- The wild-types developed amyloid plaques and other signs of AD.
- This suggests peripheral Aβ could contribute to Alzheimer’s.
The finding implies that peripheral Aβ might contribute to the development of Alzheimer’s, the authors believe. “This suggests that periphery-derived Aβ would be an important target for the prevention and treatment of AD. Alzheimer’s might be a whole-body disease,” Song and Wang wrote to Alzforum.
Other researchers were intrigued, but said it is unclear whether the finding is clinically relevant. “This is an excellent paper,” Huntington Potter, director of the Rocky Mountain Alzheimer's Disease Center in Denver, wrote to Alzforum (see full comment below). “It’s an interesting model,” agreed Lary Walker at Emory University, Atlanta. Walker noted that, in people, the brain produces much more Aβ than does the periphery, implying that any contribution of peripheral peptide to disease would be small.
Researchers emphasized that people need not worry about contracting AD from blood transfusions. Konrad Beyreuther at the University of Heidelberg, Germany, and Colin Masters at the University of Melbourne, Australia, pointed out there is no evidence of Alzheimer’s or other neurodegenerative diseases being passed along in this manner (Edgren et al., 2016). “Single blood transfusions compared to 12 months [of] parabiosis are vastly different scenarios,” Beyreuther and Masters wrote to Alzforum (see full comment below).
Aβ Infiltrates Brain. Unlike wild-type (left), parabiosis mice (middle) develop cerebral amyloid angiopathy (arrow) and amyloid plaques (arrowhead). The plaques are smaller than those in AD model mice (right). [Courtesy of Bu et al., Molecular Psychiatry.]
Previous research had found that peripheral Aβ can trigger plaque formation in AD mice, which overproduce the human peptide in the brain (Oct 2010 news; Jul 2014 news). In people, there is some evidence that peripheral Aβ can seed plaques. Researchers at University College London found amyloid plaques in the brains of young adults who had received intramuscular injections of growth hormone taken from the pituitary glands of elderly cadavers (Sep 2015 news). While these findings suggested that peripheral Aβ can enter the brain, it is unclear how big a role this route plays on its own.
Wang and colleagues set up their parabiosis experiments to distinguish the effect of peripheral Aβ from that of peptide made in the brain. First author Xian-Le Bu joined 10-month-old APPswe/PS1dE9 mice to age-matched wild-types, and analyzed how that changed the wild-type two, four, eight, and 12 months later. The scientists found human Aβ in the mouse brains starting at four months after parabiosis began. Insoluble Aβ aggregates appeared after eight months. After a year of parabiosis, the authors detected plaques in the walls of brain blood vessels and in the parenchyma surrounding the vessels. These plaques contained very little mouse Aβ, indicating that they were made almost entirely from circulating peptide. They were smaller and less extensive than the plaques found in transgenics (see image above).
Importantly, wild-type mouse brain exhibited other changes after a year of parabiosis. The amount of hyperphosphorylated tau climbed by 30 percent compared to that of age-matched controls. Activated astrocytes and microglia surrounded Aβ deposits, and levels of various pro-inflammatory cytokines roughly doubled, indicating neuroinflammation. About twice as many microhemorrhages developed as in age-matched controls. In addition, the authors detected more of the structural protein neurofilament 200 in the neurons of the neocortex, a sign of axonal degeneration.
Did these changes affect the mice’s function? The authors were unable to run behavioral experiments on the joined mice, but they measured long-term potentiation in hippocampal slices taken from them after four months of parabiosis. LTP in the parabiont wild-types was weaker than in age-matched controls, nearly matching the impairment in transgenic mice. This suggests peripheral Aβ can harm synapses, the authors noted.
This paper did not address whether peripheral Aβ was able to seed plaque formation in the brain by corrupting normal mouse protein. Nonetheless, commenters are curious about this. Beyreuther and Masters suggested trying parabiosis with APP knockout mice to determine whether the mouse peptide plays a role in plaque formation. Marco Colonna and Wilbur Song at Washington University in St. Louis wondered whether the circulating Aβ from the hAPP parabiont was produced in their periphery or the brain. “It would be interesting to see if the same phenomenon is observed with a knock-in AD model in which Aβ is only produced in brain,” they wrote (see full comment below).
Tony Wyss-Coray at Stanford University suggested that other blood-borne factors might have an effect as well. “It would be interesting to see to what extent inflammatory factors from the APP parabiont contributed to the amyloid and tau pathology in the recipient wild-type mouse,” he wrote to Alzforum (see full comment below).
Wang and Song believe that targeting peripheral Aβ might be a strategy for treating AD. They previously reported that lowering Aβ in the blood of mouse models reduced the peptide in the brain and improved memory (Xiang et al., 2015; Jin et al., 2017). They also note that people with cognitive impairment have been found to make more Aβ in platelets than do healthy people (Liu et al., 2007; Johnston et al., 2008). “We are investigating the peripheral pathogenesis of AD, and finding diagnostic biomarkers and developing therapies from this approach,” they wrote to Alzforum (Wang et al., 2017). The anti-Aβ antibody solanezumab, which fell short in Phase 3, was expected to lower plasma Aβ and thus draw it from brain, but stabilized levels in the blood (Jan 2017 news).—Madolyn Bowman Rogers
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- Solanezumab: Did Aβ ‘Reflux’ From Blood Confound Target Engagement in CSF?
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