Molecule reduces Alzheimer plaques in brain, researchers report

By Laura Lane on April 30, 2001

The highways and byways through which the brain exchanges
messages require maintenance much as any municipal road.
Crucial to these thoroughfares are the trash collectors,
which prevent the accumulation of toxic waste. What would
happen if such debris were left to accumulate?
Alzheimer’s disease would result.

Unfortunately, that scenario plays itself out over and
over again in the brains of the four million Americans
with the disease. Now, researchers at the Gladstone
Institute of Neurological Disease and the Department
of Neurology at the University of California, San
Francisco (UCSF) have identified a molecule that
could be key to getting trash-collecting cells,
called microglia, back to work.

Called TGF-b1, the molecule stimulates microglial cells
to action so they begin to clear away a toxic substance
called b-amyloid, which accumulates in Alzheimer brains
in the form of deposits, called plaques. Most surprising
is that researchers had long viewed activated microglia
primarily as the cells that incite inflammation and fuel
the disease process.

“People always thought that inflammation and microglial
activation were bad,” said Tony Wyss-Coray, PhD, lead
author, investigator at the Gladstone Institute of
Neurological Disease and assistant professor of neurology
at UCSF.  “But we showed that, when stimulated by TGF-b1,
microglial activities can be beneficial.”

Wyss-Coray and his collaborators realized they were on
to something when they measured Alzheimer-like changes
in mice that were genetically engineered with the
capability of producing both human b-amyloid and TGF-b1.
Increased levels of TGF-b1 reduced the number of plaques
by 75% and overall b-amyloid levels by 60%, compared to
mice with normal levels of TGF-b1.

For confirmation, the investigators then took microglial
cells and placed them in petri dishes along with b-amyloid.
They then added TGF-b1 to some of the dishes. Eighteen
hours later, they checked to see how much b-amyloid was
left and found that TGF-b1 had triggered the microglia
to destroy most of the b-amyloid in the dish, similar
to what happened in the mice. The results are published
in the May 2001 issue of the journal Nature Medicine.

Since TGF-b1 has many effects other than those revealed
in this study, physicians probably won’t be using
TGF-b1 to treat patients. More promising would be to
zero in on the molecules that microglia produce when
they are stimulated by TGF-b1. Such factors could be
useful for treating or preventing the accumulation of
b-amyloid in Alzheimer’s disease, Wyss-Coray explained.

Co-investigators on the study include Lennart Mucke,
MD, director of the Gladstone Institute of Neurological
Disease and Joseph B. Martin Distinguished Professor
of Neuroscience at UCSF; Gladstone research associates
Carol Lin, Fengrong Yan, Gui-Qiu Yu, and Michelle
Rohde; Lisa McConlogue, PhD, staff scientist at Elan
Pharmaceuticals; and, Eliezer Masliah, MD, professor of
pathology and neurosciences at the University of
California, San Diego.

This study was supported by grants from the National
Institute on Aging and the Alzheimer’s Association.

The Gladstone Institute of Neurological Disease is
one of three research institutes that comprise 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.