A study led by School of Medicine researchers suggests that two proteins work together to prevent the formation of brain plaques characteristic of Alzheimer’s disease in mice.
The two proteins, apolipoprotein E (apoE) and clusterin, appear to act as “chaperones” orchestrating the clearance of potentially hazardous molecules out of the brain. Ironically, these proteins also have been implicated in a key stage of plaque formation.
The study appears in the Jan. 22 issue of the journal Neuron.
“Our findings suggest it is worthwhile to explore the use of drugs or therapies to alter or perhaps increase the expression of these proteins as a potential treatment for Alzheimer’s disease,” said lead investigator David H. Holtzman, M.D., the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology.
A key step in the development of Alzheimer’s disease is the formation of brain plaques. Studies suggest these plaques form when the protein amyloid beta (Abeta) is converted from its soluble to its insoluble form and coalesces into hair-shaped threads called fibrils.
Unable to dissolve or be cleared out of the brain, the fibrils eventually clump together and become the amyloid plaques that are a hallmark of Alzheimer’s.
In previous studies, Holtzman’s team was instrumental in showing the two proteins both promote the formation of these fibrils.
The new study confirms that in mice genetically engineered to develop Alzheimer’s disease-like brain plaques, those without either apoE or clusterin developed fewer fibrils.
The team therefore expected mice lacking both proteins would develop even fewer deposits. However, the opposite was true.
Moreover, fibrils in animals lacking both proteins developed significantly earlier in life and resulted in the more advanced amyloid plaques. Such extreme Abeta deposition at a young age is akin to that in humans with the rare, genetic form of the disease called familial Alzheimer’s.
“This was an unexpected and striking result,” Holtzman said. “Though at first counter-intuitive, it implies that apoE and clusterin cooperate to suppress Abeta deposition.”
In addition to increased amounts of Abeta in brain tissue, the team found abnormally high levels in the fluid surrounding individual brain cells and in the fluid surrounding the entire brain.
In contrast, levels of Abeta in the blood were not abnormally high.
Combined, the results suggest the two proteins not only play a role in the development of fibrils, but also in the clearance of Abeta from brain tissue and surrounding fluid. Without its chaperones, Abeta protein settles in the brain and eventually clusters into plaques.
According to Holtzman, the next step is to determine whether human forms of apoE and clusterin also delay or prevent the development of plaques in the mouse model and to explore the potential for drugs or gene therapy to reverse plaque formation in mice.
Holtzman, who is also the Charlotte and Paul Hagemann Professor of Neurology and a professor of molecular biology and pharmacology, led the study.
Ronald DeMattos, Ph.D., formerly an instructor in neurology, and John R. Cirrito, a graduate student in neuroscience, are co-first authors. The team collaborated with Eli Lilly and Company, where DeMattos now works.