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