Purdue News

March 21, 2006

Purdue findings reveal possible Alzheimer's link to brain organ

WEST LAFAYETTE, Ind. — Researchers have discovered that an organ in the brain called the choroid plexus apparently plays a critical role in preventing the accumulation of a protein associated with Alzheimer's disease.

The researchers found that the choroid plexus acts as a sort of "fishnet" that captures the protein, called beta-amyloid, and prevents it from building up in the cerebrospinal fluid, which surrounds and bathes the brain and spinal cord. Moreover, tissue in the organ is able to soak up large amounts of the protein and may contain enzymes capable of digesting beta-amyloid, said Wei Zheng (pronounced Way Zsheng), an associate professor in the School of Health Sciences at Purdue University.

The findings represent the first time that researchers have identified the potential existence of a natural mechanism in the brain for removing beta-amyloid.

"This newly uncovered pathway may help explain how normal brains balance this protein and how an imbalance caused by aging, genetic or environmental factors may lead to or worsen Alzheimer's disease," Zheng said.

Researchers had already known that the cerebrospinal fluid in the brains of Alzheimer's patients contains abnormally high quantities of beta-amyloid fragments. Beta-amyloid deposits accumulate over a period of years, resulting in abnormal clumps, or plaque, typical of Alzheimer's disease. Scientists do not yet know whether the disease is caused by the plaque formations or beta-amyloids themselves.

The discovery suggests that a malfunctioning choroid plexus could allow too much of the protein to build up in the brain.

Findings are detailed in a research paper written by postdoctoral research associate Janelle S. Crossgrove, postdoctoral fellow G. Jane Li and Zheng, all in the Purdue School of Health Sciences. The researchers will be honored on April 2 with a best paper award from the Society for Experimental Biology and Medicine.

Scientists do not know how beta-amyloid is deposited in the brains of Alzheimer's disease victims, but a long-held theory is that the protein is overproduced by aging brain cells, or neurons.

"We are coming from a totally different point of view," Zheng said. "We think that a balance of beta-amyloid is maintained partly by the choroid plexus, which removes beta-amyloid, and that this balance breaks down, leading to a buildup."

The majority of Alzheimer's research has historically concentrated on how the brain produces beta-amyloid protein, but the new findings point to the possibly critical importance of the "garbage-removal" process in the choroid plexus, Zheng said.

"We think the choroid plexus plays a role of removing all the garbage, including the beta-amyloid," Zheng said.

The research focused on how the choroid plexus works to clean beta-amyloid from the cerebrospinal fluid. Studies using rat brains indicated that choroidal cells removed about five times more beta-amyloid from cerebrospinal fluid compared to how much of the protein the cells allowed to pass into the fluid.

"These results appear to tell us that a healthy choroid plexus can remove beta-amyloid from the cerebrospinal fluid, suggesting a novel pathway for the brain to maintain a normal balance," Zheng said. "Of course, much more work needs to be done to verify this theory."

The researchers also found that the choroid plexus possesses an enormous capacity to absorb beta-amyloids. The findings support the theory that the choroid plexus may possess a special enzyme that breaks beta-amyloids into smaller pieces, making it possible to soak up large quantities of the protein.

"The tissue must have a unique mechanism that is different from brain cells, something that enables it to chop up these beta-amyloids," Zheng said.

Future research may focus on efforts to isolate possible enzymes.

Zheng said the findings suggest that aging may degrade the organ's performance, and it is also possible that lead poisoning might increase the risk of Alzheimer's disease by damaging the choroid plexus and reducing its ability to filter beta-amyloids.

Alzheimer’s disease affects more than 4 million Americans, and the findings might help researchers develop new methods to treat the disease. The research paper was published last November in the journal Experimental Biology and Medicine.

Writer: Emil Venere, (765) 494-4709, venere@purdue.edu

Sources: Wei Zheng, (765) 496-6447, wzheng@purdue.edu

Janelle S. Crossgrove, (765) 494-0737, crossgrove@purdue.edu

Purdue News Service: (765) 494-2096; purduenews@purdue.edu


Note to Journalists: An electronic copy of the research paper is available from Emil Venere, (765) 494-4709, venere@purdue.edu



The Choroid Plexus Removes β-Amyloid from Brain Cerebrospinal Fluid

Janelle S. Crossgrove, G. Jane Li, and Wei Zheng
School of Health Sciences, Purdue University, West Lafayette, Indiana 47907

β-Amyloid (Aβ) concentrating in the cerebrospinal fluid (CSF) of the brain may be regulated by the choroid plexus, which forms a barrier between blood and brain CSF. Aβ uptake from CSF was determined as its volume of distribution (VD) of [125 ι]Aβ1-40 was corrected by subtraction of the VD [14 C]sucrose, a marker for extracellular space and diffusion. Aβ uptake into choroid plexus was time and temperature dependent. Uptake of [125 ι]Aβ was saturable. Aβ uptake was not affected by addition of transthyretin or apolipoprotein E3. In studies with primary culture monolayers of choroidal epithelial cells in Transwells, Aβ permeability across cells, corrected by [14 C]sucrose, was greater from the CSF-facing membrane than from the blood-facing membrane. Similarly, cellular accumulation of [125 ι]Aβ was concentrative from both directions and was greater from the CSF-facing membrane, suggesting a bias for efflux. Overall, these results suggest the choroid plexus selectively cleanses A_ from the CSF by an undetermined mechanism(s), potentially reducing A_ from normal brains and the brains of Alzheimer's disease patients. Exp Biol Med 230:771-776, 2005


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