By Jessica Hall
If it seems like we’ve been writing a lot about Alzheimer’s
lately, that’s because there have been a bunch of recent studies out
that deserve attention. Following closely in the wake of a breakthrough in our understanding of the way amyloid-beta (Aβ) and tau proteins spread through the brain in Alzheimer’s disease, a new study from the EPFL
in Lausanne has shed light from another angle on what’s going on under
the hood. Experiments with mice have shown that a tiny, flat transdermal
implant can deliver precisely engineered antibodies that clear amyloid-beta plaques (full text) from mouse brains. They’re calling it “passive immunization,” and it could be the next step on the path to a cure.
The indwelling device itself is a little flat capsule-shaped
thing, built to hold myoblasts suspended in a protective hydrogel
between two porous membranes sealed together by a tiny frame. Those
myoblasts can interact with the surrounding tissue through the permeable
membrane. They’re engineered to sit under the skin and produce specific
antibodies which can breach the blood-brain barrier, bind to the
amyloid-beta proteins in mouse brains, and tag them for destruction and
disposal by the mouse’s own immune system. In two different mouse
Alzheimer’s models, these transdermal implants dramatically reduced the Aβ plaque load.
During the experiment, some 39 weeks after implantation, the
EPFL researchers saw that the myoblasts had great survival rates and
were calmly churning out anti-amyloid antibodies at a rate sufficient to
halt their deposition and clear existing plaques from the mouse brains.
The mice laid down new vasculature to nourish the myoblasts, and even
though the engineered antibodies contained human genetic material, they
and their parent myoblasts were preserved from wholesale immune attack
by the porous containing membrane.
Furthermore, the researchers observed reduced
phosphorylation (activation) of tau protein, the other prime offender as
far as current Alzheimer’s research can tell. That even got the
attention of the Kurzweil singularity crowd, which eagerly anticipates
clinical advances capable of stalling the heretofore-inevitable creep of aging.
The fact remains that just because these protein plaques are
understood to be the primary pathology doesn’t mean removing the
plaques will be a cure for Alzheimer’s disease or anything else. Giving
in to breathless hype is the surest path to disappointment, especially
when what we have is one team working with a couple of nonhuman disease
models.
We don’t know whether removing the plaques will alleviate
the symptoms of Alzheimer’s, especially in light of the fact that
amyloid plaques accumulate as everyone ages, not just people who have
Alzheimer’s. We don’t know what other parts of the body’s amazingly
intricate proteome will have functional regions that these antibodies
could bind to, nor what will have to go wrong for us to find out.
Fiddling with the immune system tends to lead to imbalances and
inflammation –and lately, more and more diseases and syndromes are being linked with the immune component of their pathology. The moral of this story is that we need to tread carefully with regard to immune function.
Nevertheless, the way these devices perform led the Lausanne
team to conclude that this is an important breakthrough in
neurodegenerative disorders associated with protein misfolding or
aggregation. Transdermal implants are much less invasive than the
current state of the anti-Aβ-antibody treatment process,
which involves frequent injections of antibodies that end up
incurring an immune response just because of the relatively huge volume
of immunogenic particles. In their Brain writeup, the team
declared Alzheimer’s, Parkinson’s, frontotemporal dementia and ALS to be
fair game for targeting by passive immunization.
Their next step? Scaling up the implant, tweaking the
antibodies so they’re better at getting through to the brain, and moving
forward to human clinical trials.
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