. Amyloid-beta dynamics correlate with neurological status in the injured human brain. Science. 2008 Aug 29;321(5893):1221-4. PubMed.


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  1. This is a fantastic study using an extraordinarily powerful technique to study human physiology and pathophysiology. While the implications for a "normal" function of Aβ are intriguing, it is still not completely clear whether the data reflect an active role for Aβ or simply establish that it is a marker for neuronal activity. Sorting this out will be fascinating.

    The remaining other big question - hopefully soon to be determined - is what happens in Alzheimer disease? Do low CSF Aβ levels reflect low synthesis? Does the diminished rate of plaque accumulation as the disease progresses reflect low synthesis rates? Hopefully this technology can shed light on these long-standing paradoxes.

  2. This fits very nicely with accumulating evidence on the involvement of Aβ peptides in maintenance and repair. The “toxic” hydrogen peroxide Aβ produces (Behl et al., 1994) is actually a signaling molecule used by growth factors to activate many of their downstream effectors (Rhee et al., 2003). Growth factors, of course, are involved in repair as well as growth.

    Aβ produces another molecule besides hydrogen peroxide that is generally considered toxic but might actually be involved in maintenance and repair. Aβ1-42 was recently found to activate sphingomyelinases, whose product ceramide kills cells (Malaplate-Armand et al., 2006) but can also activate autophagy (Scarlatti et al., 2004), an important component of maintenance and repair systems which malfunctions in Alzheimer’s (Nixon et al., 2005).

    In fact, “toxic” ceramide has an even more surprising function. It mediates the effects of NGF on outgrowth of cultured hippocampal neurons, according to Brann et al. (1999). It seems that low levels of ceramide promote growth, intermediate levels, autophagy, and high levels, apoptosis. Since Aβ produces ceramide (see above), this means that the concentration of Aβ might be critical, too. Low levels of Aβ peptides promote neurite outgrowth, and high levels inhibit it (Postuma et al., 2000). We know that high levels kill cells, so perhaps intermediate levels promote autophagy?


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