The discovery, announced this week, of several genetic mutations
that predispose people toward Alzheimer's disease is intriguing,
because the genes are associated with cholesterol metabolism and
inflammation. The Alzheimer's jigsaw is a long way from being
complete, but the pieces are emerging, and this new evidence fits
quite nicely with the other pieces in suggesting a role for
inflammation.
Piece 1 is the immediate cause of Alzheimer's disease: the
appearance of insoluble "plaques" made of a small protein called
amyloid beta (A-beta for short) inside brain cells. These plaques
block the traffic of molecules in the cells. Eventually another
small protein, called tau, also starts to crystallize in this way
to form "tangles." Both symptoms are diagnostic of Alzheimer's, and
similar ones characterize other neurological syndromes such as
Parkinson's and Creutzfeldt-Jakob's.
Puzzle piece 2 is the APOE gene on chromosome 19, long known as
a powerful influence on whether you will get Alzheimer's disease.
Having two copies of the 4 version of the gene makes you 20 times
more likely than average to get the symptoms before the age of 75.
(Having at least one copy of the 2 version makes you less likely
than average to get the symptoms.) One of APOE's jobs is to break
down plaques, and the 4 version is inefficient at this task.
So right at the heart of the disease is the insolubility of
proteins in old age. Proteins in living cells always teeter on the
edge of insolubility, because with so many different proteins
dissolved in the cell doing different jobs, the total concentration
is high and crystallization is a risk. Solubility depends on the
correct folding of each protein into a certain shape. With even
slight misfolding, a protein may crystallize too easily.
Here is piece 3 of the puzzle. Prof. Chris Dobson of Cambridge
University made 17 slight genetic adjustments to the A-beta protein
to make it either more or less soluble. He then genetically
engineered the mutant proteins into fruit flies and showed that the
less soluble the protein, the less coordinated and the
shorter-lived were the fruit flies. In effect, by lining up the
test-tubes, he could make the dancing flies form a sort of living
graph of solubility versus activity.
What makes misfolded proteins appear in elderly brains? Piece 4:
Cells have an internal quality-control mechanism that both detects
and refolds misfolded proteins. Research published last month by
scientists at Brown University revealed that both parts of this
mechanism-the detector and the refolder-are working, but
overwhelmed, in diseased brains; they can't keep up with the
workload of too many misfolded A-beta proteins.
Which brings us to piece 5, this week's announcement of the
discovery by Jeffery Kelly and his colleagues at the Scripps
Research Institute that a chemical formed when cholesterol reacts
with ozone attaches to A-beta and makes the misfolding of it more
likely. The ozone comes from inflammation.
Piece 6 is stress-caused by worry, fear, pain, trauma-which
shows itself in the production of cortisol, a hormone made from
cholesterol. Cortisol, too, is beginning to look like an accomplice
in the misfolding of A-beta, according to work at the University of
California at Irvine.
So we can begin to tell a coherent story. Stress and
inflammation produce derivatives of cortisol and cholesterol, which
trigger misfolding in A-beta proteins. This, in turn, overwhelms
the cells' quality-assurance mechanism and results in growing
numbers of insoluble proteins, which aggregate in plaques and
tangles. And this blocks the transport of vital ingredients around
brain cells, which causes the cells to die.
Somewhere along this chain, there is a link, we must hope, that
can be attacked by medication-to prevent inflammation, discourage
ozone reactions, encourage the refolding apparatus, improve protein
solubility or boost the plaque-removal mechanism.
