Gladstone researchers find clue to Alzheimer's disease risk factor

For years, scientists have recognized that a protein called
apoE4 is a major risk factor for developing Alzheimer’s
disease. Researchers at the Gladstone Institute of Neurological
Disease now demonstrate how apoE4 alters the ability of nerve
cells to maintain their normal internal framework, or
cytoskeleton, which is important to the survival and function
of the nerve cells.

Published in the July 17 issue of the Proceedings of the
National Academy of Sciences, the study shows how apoE4
could cause the formation of neurofibrillary tangles, one
of two pathological hallmarks of Alzheimer’s that are
presumed to contribute to the degeneration of neurons
in this disease. The tangles represent an abnormal buildup
of various nerve cell cytoskeletal proteins, which may
contribute to brain cell damage.

ApoE4 is formally called apolipoprotein E4 and is one of
three forms of a group of apolipoproteins. The other two are
called apoE2 and apoE3 and are not risk factors for Alzheimer’s.
Anywhere from 40 to 60 percent of patients with Alzheimer’s
carry apoE4.

The present study demonstrates that the apoE4 taken up by
or made specifically by nerve cells is cut by an unknown
enzyme, which activates the apoE fragment in such a way
that it interacts with the intracellular cytoskeletal proteins,
called tau and neurofilaments, to form neurofibrillary
tangle-like structures.

“This is a significant step that suggests how apoE4 might
disrupt the ability of brain cells to interact and interconnect,”
said co-author Robert W. Mahley, MD, PhD, senior Gladstone
investigator and UCSF professor of pathology and medicine.
“The cleavage of apoE4 to create an active fragment provides a
mechanism whereby apoE can alter the structure and function of
the cytoskeleton, precipitate the cytoskeletal proteins to form
the tangle-like structures, and impair normal nerve cell function.”

Previously, Gladstone scientists have shown that apoE4 interferes
with the ability of nerve cells to send out the long cellular
processes that connect one cell to another, whereas apoE3 and
apoE2 promote the formation of these connections. A normal
cytoskeleton within nerve cells is required for the cells in
the nervous system to establish their connections and to transmit
impulses or messages important in memory, learning, and other
neurological functions.

Identifying the enzyme that clips and activates the apoE could
lead to the development of an Alzheimer’s disease treatment,
said lead author Yadong Huang, MD, PhD, Gladstone investigator
and UCSF assistant professor of pathology.

“When we find the enzyme that cleaves apoE4, then we can design
an inhibitor to block its action and, possibly, alter the
progress of the disease,” he said.

The researchers first examined the brains of deceased
Alzheimer’s patients and found that the neurofibrillary tangles
were composed of truncated versions of apoE4, along with
cytoskeletal proteins. The next piece of evidence came from
studies of cells grown in culture. Examining those that
express apoE4 and apoE3 showed that the unknown enzyme was
more likely to cut apoE4 than apoE3 and that the truncated
form of apoE4 was more active in forming the tangle-like
structures in the nerve cells. Cells from peripheral organs
that were made to express apoE4 and apoE3 did not form any
tangle-like structures.

The researchers don’t know exactly why apoE4 is so much more
susceptible to being cut to form the active fragment, but
Huang speculated that the reason could lie in the three-
dimensional structure of the protein.

The cells expressing apoE4 were also more likely to contain
clumps that resemble neurofibrillary tangles. About 78
percent of nerve cells that expressed truncated apoE4
contained neurofibrillary tangle-like structures. These
tangles were only present in 32 percent of nerve cells
expressing truncated apoE3.

Co-investigators of this study include Xiao Qin Liu, MD,
research associate, Walter J. Brecht, senior research
associate, and David A. Sanan, PhD, staff research scientist,
all of the Gladstone Institute for Cardiovascular Disease;
and Tony Wyss-Coray, PhD, staff research investigator at the
Gladstone Institute of Neurological Disease and UCSF assistant
professor of neurology.

This study was funded by the J. David Gladstone Institutes.

The Gladstone Institute of Neurological Disease is one of
three research institutes that compose The J. David Gladstone
Institutes, a private biomedical research institution
affiliated with UCSF. The institution is named for a prominent
real estate developer who died in 1971. His will created a
testamentary trust that reflects his long-standing personal
interest in medical education and research.