Consciousness and how it got to be that way

Monday, July 1, 2013

Why Can't We Create APP Knockout Humans?

You will either die from Alzheimers disease, or from something else first. This of course is trivial, but Alzheimers is now the third leading cause of death in the U.S. and it's on track to become the second in the next few decades. In Japan it may already be the second, surpassing heart disease. AD can only be truly diagnosed at autopsy, but the majority of us have detectable plaques in our brains by the time we're in our 70s, whether or not we're showing clinical symptoms. The treatments we have so far merely attempt to slow the damage, and they can't even do that well; we've just learned that the (earlier-stage) oligomers are structurally different from the full plaques, which may be why the molecules we've thrown at the plaques don't interact well.

Thinking speculatively, what happens if we prevent the whole plaque formation problem - which really does seem to be an issue of humans living well past our paleolithic warranty period - by knocking out the amyloid precursor protein altogether in our descendants? Knockout mice have been around for a while; what's their phenotype like? Not great. They demonstrate:

reduced weight
decreased neuromuscular performance
reactive gliosis in the hippocampus & cortex (later in adult life)
reduced synaptic plasticity
loss of synaptic immunoreactivity for:
defects in the corpus callosum
This does not sound like an opportunity for enhancement. Original paper here.

The knockout mice also do much worse in a cerebral ischemia paradigm, related to the reactive gliosis seen in the list. If APP is involved with resistance to or recovery from infarct, this is consistent with the observed increase in Alzheimers and amyloid plaque formation in humans after cerebral infarcts.

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