Beta Amyloid: Not just for Alzheimer’s Anymore
This is the third option for “things I could present in Journal Club”. Please let me know if you have a strong preference! The Journal Club is, um, tomorrow. So I probably better get my rear in gear.
As I’m sure you all know, Alzheimer’s Disease is a serious problem in today’s aging population, affecting 26.6 million people around the world. Diagnoses of Alzheimer’s are growing, mostly due to the fact that no one’s ever lived this long before, and we’re able to catch it at earlier and earlier stages now. Alzheimer’s is one scary problem. It’s incurable (so far), degenerative (gets worse over time), and terminal. Almost every time I read about Alzheimer’s I get really paranoid for a while as to WHY I’m forgetting my car keys.
Alzheimer’s has a very characteristic set of symptoms: cognitive impairment and memory loss which increases over time, language and mild motor impairments, progressive loss of skills, and psychiatric manifestations such as irritability or aggression. The pathophysiology of Alzheimer’s involves the build up of beta-amyloid plaques, as well as the buildup of tau proteins. Beta amyloid gets misfolded in Azheimer’s patients, and aggregates outside cells, sticking in clumps everywhere. Tau proteins are usually used to stablize the cytoskeleton of the cell, but when these go bad, they cuase microtubules to join to each other all over the place, making neurofibrillary tangles inside the cell.
Unfortunately, although we know what the tau protein does inside cells, we don’t really have a clear idea what beta amyloid does hanging outside the cell in general. So this study looked at the changes taking place in beta amyloid by taking samples in humans.
Brody et al. “Amyloid-B dynamics correlate with neurological status in the injured human brain”. Science, 321, 2008.

Now, microdialysis is a pretty invasive procedure. It usually involves drilling a hole in the skull, and putting a probe in through the hole (this is in animals, humans always put up such a fuss about it for some reason). The probe is a tiny little tube, through which you flow artificial cerebrospinal fluid, similar to the fluid that is already in your brain. But the artifical fluid has no proteins, neurotransmitters, or other endogenous molecules in it. So as the artifical fluid flows slowly through the brain, the endogenous molecules will diffuse past the membrane into the tube, trying to make the fluid in the tube come to equilibrium with what is already in the brain. When the artifical fluid comes out, then, it has a pretty good sampling of what is in your brain, and we can analyze the sample to determine exactly what is there and how much of it there is.
Because microdialysis is invasive, it’s not used very often in humans, though it has provided amazing amounts of information on neurochemistry and physiology from work done in animals. In this particular study, however, microdialysis was done in the brains of humans. While we have freely-moving microdialysis in things like mice, rats, and monkeys, it’s hard to confine a human to a relatively small space, and to make a cord attachment that would give them freedom of movement. So these humans were lying very still. VERY still.
The patients used in this study were patients in the ICU for severe head trauma, and microdialysis experiments were being done. Probably the samples were being used for a lot of different purposes (depending on the technique, you can get enough definition to see a cell sneeze if you’re so inclined), but the authors here lookd at beta-amyloid. None of the patients were known to have Alzheimer’s or dementia in the first place, so this was a very good excuse to look at how beta-amyloid is regulated in brains that are not afflicted with Alzheimer’s.
What the authors found was that several kind of beta-amyloid were already present in the brain. One of them was AB(1-42), the form that appears to move toward Alzheimer’s the easiest by aggregating into plaques, but the concentrations were very low compared to normal kinds of beta-amyloid.
The authors discovered that beta-amyloid levels in the extracellular fluid varied mostly according to the patient’s state. Beta-amyloid levels were lowest when the patient was worst, when there were high levels of lactate and pyruvate around, low glucose, and high pressure (times when there’s not a lot of blood getting to the brain). Beta-amyloid levels got higher as the patient got better, and as their brains appeared to be recovering, and levels of beta-amyloid correlated very nicely with the Glasgow Coma Score, showing that beta-amyloid levels were highest when a patient was closest to awake and responding normally.
So what does this mean? It appears that beta-amyloid levels are highest when brains are better, implying that they are either a measure or product of healthy cell activity, or that they are regulated extensively by normal cell activity. This provides the first insight in to the role that beta-amyloid might play in a normal human brain (well, relatively normal. At least a brain that didn’t have Alzheimer’s). And knowing what beta-amyloid does normally is the first step to finding how they screw up, and what we can do about it.
D. L. Brody, S. Magnoni, K. E. Schwetye, M. L. Spinner, T. J. Esparza, N. Stocchetti, G. J. Zipfel, D. M. Holtzman (2008). Amyloid- Dynamics Correlate with Neurological Status in the Injured Human Brain Science, 321 (5893), 1221-1224 DOI: 10.1126/science.1161591

One Response

  1. This one! You should include some attention to Mark Smith (and a few others) with their ‘amyloid is protective’ hypothesis; and also to the links between energy state (proxied by glucose levels; both hypo- and hyperglycemia appear to cause problems) and amyloid accumulation/AD.
    Definitely a strong vote :).

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