synapse-traveling molecules went hay-
wire. “Nerve circuits couldn’t perform
properly anymore, and the mouse
couldn’t learn or remember properly,”
Mucke says. “The whole information
processing pathway comes apart.”
Mucke and his colleagues reversed
these memory deficits in mice carrying
heavy loads of A-beta by boosting levels
of the EphB2 protein. Studies show that
people with Alzheimer’s have less Eph B2
in their brain cells, so protecting the pro-
tein from A-beta or artificially boosting
its levels might be a way to reverse cogni-
tive decline, Mucke says.
A-beta may also hit another target
at the synapse. In mouse brains with
high levels of A-beta, a protein called
Caspase- 3 was busier than normal, a
dangerous hyperactivity that led to
the disintegration of dendrites, a nerve
cell’s message-receiving extensions.
This A-beta–Caspase- 3 combo caused
dendrites’ demise in the hippocampus,
the brain’s center for forming memo-
ries, researchers reported in the January
issue of Nature Neuroscience. Dampen-
ing Caspase- 3’s activity protected these
dendrites, suggesting that, like EphB2,
Caspase- 3 might be a good place to inter-
vene to protect nerve cell communica-
tion from Alzheimer’s disease.
These assaults at the synapse were led
by diminutive forms of A-beta called
oligomers. Small, dissolvable pieces of
A-beta, they are the building blocks of
the large, insoluble fibrils that form the
plaques first spotted by Alois Alzheimer.
Oligomers are quickly gaining notoriety
as a more probable villain than the well-studied plaques.
Data from neuroscientist Caleb
Finch’s group at the University of Southern California in Los Angeles, and work
by other researchers, have made the case
that the oligomers are the most damaging form of A-beta. “We are convinced
Amyloid on the brain though amyloid-beta has long been implicated in alzheimer’s disease, figuring out just how the protein harms the brain
has proved tricky. a-beta appears to cause problems when it aggregates into other forms and accumulates, perhaps because of overproduction or
slow clearance. in its small oligomer form, a-beta can damage synapses, message-relaying connections between nerve cells. by setting off cascades
of reactions, oligomers can also damage neural extensions called dendrites. oligomers can clump into fibrils, which then form the large amyloid
plaques characteristic of the disease. Many other potential culprits are also being investigated, some of which alter a-beta activity and some of which
appear to cause damage in different ways.
Dendrite
Synapse
Oligomers
Neuron
A-beta
intermediate
Amyloid-beta
Plaque
Amyloid
precursor
protein
Fibrils
