. 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. Amyloid-β Shows Another Facet
    In this article, Brody et al. showed that concentrations of amyloid-β (Aβ) in brain interstitial fluid (ISF), in vivo, increased following head injury and subarachnoid hemorrhage as neurological status improved. Conversely, concentrations of Aβ fell when neurological status declined. The authors conclude that neuronal activity regulates the concentration of extracellular Aβ, and that declining levels of Aβ reflect depressed neuronal function.

    To some extent, Brody et al. underestimate the potential significance of their findings. As emphasized by the authors, observations derived from in vivo studies in human patients are extremely valuable as they relate directly to the human condition and allow the generation of hypotheses that can be tested experimentally. In addition, their studies have produced data regarding the physiological functions of soluble Aβ that are relevant to the role of Aβ in Alzheimer disease (AD).

    A number of recent studies suggest that soluble Aβ in the brain may have a more significant role in the pathogenesis of AD than the plaques of insoluble Aβ. PET imaging has shown that, as a group, patients with mild cognitive impairment have a similar amount of insoluble Aβ in their brains as patients with AD [3]. Furthermore, removal of Aβ plaques from the brain does not prevent progressive neurodegeneration in AD [2]. Other studies indicate that high levels of soluble Aβ in the brain correlate more closely with cognitive decline in AD than does insoluble Aβ plaque load [5,6] and that removal of Aβ plaques from the brain by Aβ immunotherapy increases the level of soluble Aβ in the brain [8].

    The perceived role of soluble Aβ in the pathogenesis of cognitive impairment in AD makes it all the more urgent to take a fresh look at the physiological and pathological roles of Aβ. Little is known about the physiological role of soluble Aβ in the brain in vivo. The result’s of Brody et al. suggest that neurons produce Aβ in response to acute brain injury and that the higher levels of Aβ in the subcortical white matter correlate with improvement of neurological status. But, why should the levels of soluble Aβ rise in those patients showing improvement in neurological status?

    Levels of soluble Aβ in the brain depend not only on its level of production but also on the efficiency of elimination of Aβ from the interstitial fluid [11]. Several pathways for elimination of Aβ are recognized; they include degradation by neprilysin and absorption into the blood by various mechanisms [11]. Aβ also drains with brain ISF along basement membranes in the walls of cerebral capillaries and arteries where it may deposit as cerebral amyloid angiopathy (CAA) [11]. The rise in concentration of Aβ in the ISF during the recovery period following acute brain injury in the study of Brody et al. could reflect a reduction of elimination of Aβ as well as its increased production.

    Failure of elimination of Aβ along perivascular drainage routes and the development of CAA is observed with increasing age when arteries stiffen [11] and following denervation [1] when vessel tone may be affected. Diffuse vascular injury is well recognized in patients with head injuries [9], and vascular spasm is seen in both head injury and following subarachnoid hemorrhage [7]. Vascular factors may play a role in impeding the elimination of Aβ along artery walls and in the development of CAA following head injury [4].

    Brody et al. emphasize that their results correlate with in vitro studies showing that neuronal and synaptic activity dynamically regulates the concentration of extracellular soluble Aβ. However, it is not known whether the effects of the increased production of Aβ are purely local or whether Aβ has an effect on artery walls as it drains out of the brain along perivascular pathways.

    The role of Aβ in the pathogenesis of AD requires some re-evaluation. Aβ in its soluble form in the brain seems to be as important as insoluble plaques of Aβ, if not more important, in the pathogenesis of AD. Toxic forms of soluble Aβ appear to have a role in the pathogenesis of AD [10], and the techniques used by Brody et al. may provide the opportunity to study this further in vivo. However, we may ask whether toxicity is the sole role for Aβ in AD. The deposition of fibrillar Aβ in the perivascular drainage pathways in CAA may block the elimination not only of Aβ but also of other brain metabolites. This may lead to loss of homeostasis and neuronal malfunction as a factor in cognitive impairment in AD. Evaluation of the composition of brain ISF may help to answer questions about the quality of the neuronal environment in patients with AD.

    View all comments by Roy Weller
  3. 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?

    References:

    . Hydrogen peroxide mediates amyloid beta protein toxicity. Cell. 1994 Jun 17;77(6):817-27. PubMed.

    . Ceramide signaling downstream of the p75 neurotrophin receptor mediates the effects of nerve growth factor on outgrowth of cultured hippocampal neurons. J Neurosci. 1999 Oct 1;19(19):8199-206. PubMed.

    . Soluble oligomers of amyloid-beta peptide induce neuronal apoptosis by activating a cPLA2-dependent sphingomyelinase-ceramide pathway. Neurobiol Dis. 2006 Jul;23(1):178-89. PubMed.

    . Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol. 2005 Feb;64(2):113-22. PubMed.

    . Substrate-bound beta-amyloid peptides inhibit cell adhesion and neurite outgrowth in primary neuronal cultures. J Neurochem. 2000 Mar;74(3):1122-30. PubMed.

    . Cellular regulation by hydrogen peroxide. J Am Soc Nephrol. 2003 Aug;14(8 Suppl 3):S211-5. PubMed.

    . Ceramide-mediated macroautophagy involves inhibition of protein kinase B and up-regulation of beclin 1. J Biol Chem. 2004 Apr 30;279(18):18384-91. PubMed.