New insight on brain cell metabolism during onset of Alzheimer's
23 April 2013
Researchers from Karolinska Institutet in Sweden have shown, for
the first time, how important parts of the nerve cell that are
involved in the cell’s energy metabolism operate in the early stages
of Alzheimer’s disease. These surprising results shed new light on
how neuronal metabolism relates to the development of the disease.
In the Alzheimer’s disease brain, plaques consisting of so called
amyloid-beta-peptide (Aβ) are accumulated. It is also a well-known
fact that the nerve cells of patients with Alzheimer’s disease have
problems metabolising for example glucose and calcium, and that
these disorders are associated with cell death. The metabolism of
these substances is the job of the cell mitochondria, which serve as
the cell’s power plant and supply the cell with energy.
However, for the mitochondria to do this, they need good contact
with another part of the cell called the endoplasmic reticulum (ER).
The specialised region of ER that is in contact with mitochondria is
called the MAM region. Earlier studies on yeast and other types of
cells have shown that the deactivation of certain proteins in the
MAM region disrupt the contact points between the mitochondria and
the ER, preventing the delivery of energy to the cell and causing
Now for the first time, researchers at Karolinska Institutet have
studied the MAM region in nerve cells, and examined the interaction
between the mitochondria and the ER in early stage Alzheimer’s
disease. Although at this point in the development of the disease Aβ
has not formed large, lumpy plaques, symptoms still appear, implying
that Aβ that has not yet formed plaque is toxic to neurons.
The team’s results are slightly surprising. When nerve cells are
exposed to low doses of Aβ, it leads to an increase in the number of
contact points between the mitochondria and the ER, causing more
calcium to be transferred from the ER to the mitochondria. The
resulting over-accumulation of calcium is toxic to the mitochondria
and affects their ability to supply energy to the nerve cell.
“It’s urgent that we find out what causes neuronal death if we’re
to develop molecules that check the disease,” says Maria Ankarcrona,
docent and researcher at the Department of Neurobiology, Care
Sciences and Society, and the Alzheimer’s Disease Research Centre of
Karolinska Institutet. “In the long run we might be able to produce
a drug that can arrest the progress of the disease at a stage when
the patient is still able to manage their daily lives. If we can
extend that period by a number of years, we’d have made great gains.
Today there are no drugs that affect the actual disease process.”
The researchers conducted their studies on mice bred to develop
symptoms of Alzheimer’s disease. They also studied nerve cells from
deceased Alzheimer’s patients and neurons cultivated in the
Hedskog L et al. Modulation of the ER-mitochondria
interface in Alzheimer’s disease and related model. Proceedings of
the National Academy of Sciences (PNAS), online 22-26 April 2013.