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October 31, 2017

Alzheimer’s May Start in Body, Not Just Brain

Alzheimer's disease pathologies may arise from blood-derived amyloid-beta protein, report scientists who experimented with surgically joined mice. When transgenic Alzheimer’s disease mice shared blood circulation with normal mice, the normal mice formed cerebral amyloid angiopathy and amyloid-beta plaques. [University of British Columbia]

  • Alzheimer’s disease may move, cancer like, from place to place in the body, lodging in the brain after originating in peripheral tissues. Just how much Alzheimer’s begins in the body as opposed to the brain remains unclear. But Alzheimer’s of bodily origin could justify the search for drugs that would attack the disease before it could cross the blood–brain barrier, which weakens as we age. Such drugs could target the kidney or liver, rather than act directly on the brain, which is complex, sensitive, and often hard to reach.

    The cancer-like mobility of Alzheimer’s disease was demonstrated through a technique called parabiosis—the surgical union of two specimens to allow them to share a blood supply. This technique was used by scientists based at the University and British Columbia (UBC) and Third Military Medical University in Chongqing to keep pairs of mice together for several months. Normal mice, which don't naturally develop Alzheimer's disease, were joined to transgenic Alzheimer’s disease mice, that is, mice modified to carry a mutant human gene that produces high levels of amyloid-beta (Aβ).

    Aβ, a protein that can form plaques and smother brain cells, is generated in both brain and peripheral tissues. Although it is believed that Aβ that clumps in the brain originates from brain tissue itself, the parabiosis study was designed to evaluate whether circulating Aβ could contribute to brain pathologies resembling Alzheimer’s disease.

    Detailed results from the study appeared October 31 in the journal Molecular Psychiatry, in an article entitled “Blood-Derived Amyloid-β Protein Induces Alzheimer’s Disease Pathologies.” The article presented the observation that human Aβ originating from transgenic Alzheimer’s disease mice entered the circulation and accumulated in the brains of wild-type mice, forming cerebral amyloid angiopathy and Aβ plaques after a 12-month period of parabiosis.

    “AD [Alzheimer's disease]-type pathologies related to the Aβ accumulation including tau hyperphosphorylation, neurodegeneration, neuroinflammation and microhemorrhage were found in the brains of the parabiotic wild-type mice,” the authors of the study detailed. “More importantly, hippocampal CA1 long-term potentiation was markedly impaired in parabiotic wild-type mice.”

    The article’s senior authors, UBC’s Weihong Song, Ph.D., and Chongqing’s Yan-Jiang Wang, M.D., Ph.D., emphasized that the Aβ traveled from the genetically modified mice to the brains of their normal partners, where it accumulated and began to inflict damage. The normal mice not only had accumulated plaques, they also developed a pathology similar to "tangles"—twisted protein strands that form inside brain cells, disrupting their function and eventually killing them from the inside-out.

    Other signs of Alzheimer's-like damage included brain cell degeneration, inflammation, and microbleeds. In addition, the ability to transmit electrical signals involved in learning and memory—a sign of a healthy brain—was impaired, even in mice that had been joined for just four months.

    Besides the brain, Aβ is produced in blood platelets, blood vessels, and muscles, and its precursor protein is found in several other organs. But until these experiments, it was unclear if Aβ from outside the brain could contribute to Alzheimer's disease. This study, asserted Song, shows it can.

    "The blood–brain barrier weakens as we age," noted Song. "That might allow more Aβ to infiltrate the brain, supplementing what is produced by the brain itself and accelerating the deterioration."

    Song envisions a drug that would bind to Aβ throughout the body, tagging it biochemically in such a way that the liver or kidneys could clear it. "Alzheimer's disease is clearly a disease of the brain,” he stated, “but we need to pay attention to the whole body to understand where it comes from, and how to stop it."

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