The scientists attached normal mice, which don’t naturally develop Alzheimer’s disease, to mice modified to carry a mutant human gene that produces high levels of the protein called amyloid beta.

Alzheimer’s disease, the leading cause of dementia, has long been assumed to originate in the brain but new research indicates that it could be triggered by breakdowns elsewhere in the body.

The findings, published today in Molecular Psychiatry, offer hope that future drug therapies might be able to stop or slow the disease without acting directly on the brain, which is a complex, sensitive and often hard-to-reach target. Instead, such drugs could target the kidney or liver, ridding the blood of a toxic protein before it ever reaches the brain.

“Alzheimer’s disease is clearly a disease of the brain, but our research shows that we need to pay attention to the whole body to understand where it comes from, and how to stop it,” said Dr. Weihong Song, UBC psychiatry professor.

Dr. Song and Yan-Jiang Wang, a neurology professor at the Third Military Medical University in Chongqing, China, demonstrated the mobility of a protein linked to Alzheimer’s disease through a technique called parabiosis. The technique involves surgically attaching two specimens together so they share the same blood supply for several months.

The scientists attached normal mice, which don’t naturally develop Alzheimer’s disease, to mice modified to carry a mutant human gene that produces high levels of the protein called amyloid beta. In people with Alzheimer’s disease, that protein ultimately forms clumps, or “plaques,” that smother brain cells.

They found that normal mice joined to genetically-modified partners for one year “contracted” Alzheimer’s disease. Song says the amyloid beta traveled from the genetically-modified mice to the brains of their normal partners, where it accumulated and began to inflict damage.

Not only did the normal mice develop plaques, but also “tangle”-like pathology, which are 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, amyloid beta 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 amyloid beta from outside the brain could contribute to Alzheimer’s disease. This study, Song says, shows it can.

“The blood-brain barrier weakens as we age,” says Song, a Canada Research Chair in Alzheimer’s Disease and the Jack Brown and Family Professor. “That might allow more amyloid beta to infiltrate the brain, supplementing what is produced by the brain itself and accelerating the deterioration.”

Song, head of UBC’s Townsend Family Laboratories, envisions a drug that would bind to amyloid beta throughout the body, tagging it biochemically in such a way that liver or kidney could clear it.

Source: UBC