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Researchers Reveal Insidious Role Of A "Serpin" In Alzheimer's Disease

Date:
December 6, 2000
Source:
University Of California, San Francisco
Summary:
Researchers led by investigators at the Gladstone Institute of Neurological Disease and the University of California, San Francisco have discovered that the protein alpha1-antichymotrypsin can double the accumulation of Alzheimer's disease-associated amyloid plaque in the brains of mice, suggesting a possible new target for therapy in humans.

Researchers led by investigators at the Gladstone Institute of Neurological Disease and the University of California, San Francisco have discovered that the protein alpha1-antichymotrypsin can double the accumulation of Alzheimer's disease-associated amyloid plaque in the brains of mice, suggesting a possible new target for therapy in humans.

Alpha1-antichymotrypsin (ACT) is a serin protease inhibitor, or serpin, that normally prevents enzymes known as proteases from digesting proteins. Scientists have known for some time that production of ACT is increased in the brains of patients with Alzheimer's disease, where it is bound tightly to amyloid proteins in abnormal deposits called plaques. These plaques, along with tangled nerve fibers known as neurofibrillary tangles, are the main pathological hallmarks of Alzheimer's disease.

However, researchers have not known whether ACT counteracts or augments the build-up and possible toxicity of amyloid proteins. Some previous studies performed in cultured cells or with proteins themselves have found that ACT decreases the aggregation of amyloid proteins, while others have found the opposite effect or no effect at all.

The current study, conducted in genetically engineered mice, reveals that increased production of ACT in the brain strongly increases the build-up of amyloid proteins, which is associated with damage to brain cells within and around the plaques.

"We speculate that reducing or inhibiting the plaque-enhancing activity of ACT could help prevent the accumulation of plaques in the brain," says the lead author of the study, Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease at the UCSF-affiliated San Francisco General Hospital Medical Center, and Joseph B. Martin Distinguished Professor at UCSF.

"There's a sneakiness to this protein," Mucke says. "While the association of ACT with plaques has been known for more than ten years, the true nature of its activity in the brain has remained elusive for all this time. Our study now demonstrates that ACT insidiously increases the plaque burden in the aging brain."

The researchers report their findings in the December issue of American Journal of Pathology.

The discovery offers one more factor to consider in the ongoing efforts to prevent the formation of amyloid plaques in the brain. Researchers from Elan Pharmaceuticals recently reported that vaccinating mice with an amyloid beta peptide, a protein component of the amyloid plaque, prevented plaque deposition, and this finding has propelled the vaccine into human clinical trials.

Researchers still do not know whether the amyloid plaques or some of their components are responsible for the degeneration of brain cells and their connections, which underlie the cognitive decline in Alzheimer's disease, such as memory loss, anxiety, confusion and, ultimately, severe dementia.

Most likely, says Mucke, several factors contribute to both the brain damage and cognitive impairment in Alzheimer's disease. As the behavior of the transgenic mice was not tested in the investigators' mouse model, it is not clear whether the increased plaque load affected cognition.

In their study, the investigators compared mice genetically engineered to produce just amyloid proteins with those producing just ACT and those producing both amyloid proteins and ACT. Mice that expressed ACT alone did not develop amyloid plaques, while mice expressing either amyloid proteins or amyloid proteins with ACT developed typical Alzheimer's disease-like amyloid plaques.

Most important, mice producing amyloid proteins plus ACT had double the amount of plaques as mice producing amyloid proteins without ACT. This was true for mice at all ages examined, including 6-8 months (adult), 14 months (middle aged), and 20 months (old). The mice also developed swelling and abnormal twisting of the branches of the nerve cells near the plaques. These "neuritic plaques" are also found in the human disease.

The increased amyloid burden in the transgenic mice producing both amyloid protein and ACT did not increase the destruction of synaptic contacts between brain cells over that found in mice producing amyloid proteins without ACT, a finding that is consistent with previous research. Most likely, says Mucke, that destruction is caused by a soluble form of the peptide that floats between the plaques.

"The amyloid-enhancing effect of ACT we demonstrated in our study suggests that ACT might be an interesting target for therapeutic interventions," says Mucke. "Our next step will be to explore the mechanism through which this factor acts. Possibilities include that it promotes the assembly of amyloid proteins and that it prevents their degradation and clearance from the brain."

Co-investigators of the study were senior author Eliezer Masliah, MD, professor of pathology and neurosciences at University of California, San Diego; Carmela R. Abraham, PhD, professor of biochemistry and medicine at Boston University; Gui-Qiu Yu, MS, research associate at the Gladstone Institute of Neurological Disease; Lisa McConlogue, PhD a scientist at Elan Pharmaceuticals; and Edward M. Rockenstein, BS, UCSD staff research associate.

The research was supported by grants from the National Institute on Aging.


Story Source:

The above story is based on materials provided by University Of California, San Francisco. Note: Materials may be edited for content and length.


Cite This Page:

University Of California, San Francisco. "Researchers Reveal Insidious Role Of A "Serpin" In Alzheimer's Disease." ScienceDaily. ScienceDaily, 6 December 2000. <www.sciencedaily.com/releases/2000/12/001206080530.htm>.
University Of California, San Francisco. (2000, December 6). Researchers Reveal Insidious Role Of A "Serpin" In Alzheimer's Disease. ScienceDaily. Retrieved July 28, 2014 from www.sciencedaily.com/releases/2000/12/001206080530.htm
University Of California, San Francisco. "Researchers Reveal Insidious Role Of A "Serpin" In Alzheimer's Disease." ScienceDaily. www.sciencedaily.com/releases/2000/12/001206080530.htm (accessed July 28, 2014).

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