When it comes to the biological activity of Aβ, a question often pondered is: How much is enough? In the March 31 Journal of Neuroscience, Barry Festoff and colleagues suggest that the answer may be: Not that much. Festoff, from the Veterans Affairs Medical Center, Kansas, together with coworkers there and elsewhere, suggest a mechanism whereby Aβ may cause neurotoxicity in the very early stages of Alzheimer’s disease. They report that levels of soluble Aβ that have no direct effect on microglia can nevertheless potentiate the effect of other molecules, namely, G protein-coupled receptor (GPCR) agonists.
This type of subthreshold response to Aβ has been observed previously in vascular cells (for example, see Wang et al., 2000). To test if microglia behaved similarly, first author Zhiming Suo and colleagues exposed primary mouse brain microglial cultures to GPCR activators, such as thrombin, after treating the cells with levels of Aβ that do (about 2.5 micromolar) or do not (around 0.01 to 0.1 micromolar) evoke a response when given alone. Suo found that in the latter case, the subthreshold level as much as tripled thrombin-induced expression of TNF-α.
So how could Aβ affect thrombin signaling? Because thrombin activates GPCRs, which must then be deactivated, Suo wondered if Aβ may prevent inactivation of these receptors. To test this idea he examined the effect of Aβ on G protein receptor kinases (GRKs), which are known to desensitize some GPCRs. The authors found that binding of GRK2 or GRK5 to two GPCRs—PAR1 and PAR4—is significantly reduced in the presence of subthreshold levels of Aβ. This, the authors discovered, may be the result of a compartmentalization effect. In the presence of Aβ1-42, GRK5 was rapidly moved from the membrane, where it is needed to switch off the GPCRs, to the cytosol. Though Aβ1-40 had a weaker effect on GRK5, and Aβ40-1 had no effect on the location of either kinase, GRK2 was unaffected by any version of the peptide.
These results are noteworthy for two reasons. First, they demonstrate that thresholds depend on what one is measuring. Second, they propose a potential mechanism for Aβ toxicity. The authors found that in the cortex of transgenic CRND8 mice, which exhibit early-onset AD symptoms, GRK2 (and GRK5) appeared to be redistributed from the membrane fraction to the soluble fraction as the animals aged. This shift became “statistically significant at 10 weeks of age, which was one week before cognitive decline or ‘disease onset’ in these animals,” write the authors. Oddly enough, some molecular modeling predictions suggest that presenilin may be a GPCR (see ARF related news story), perhaps linking Aβ back to its maker via a GRK.—Tom Fagan
- Wang Z, Natte, Berliner, van Duinen, Vinters. Toxicity of Dutch (E22Q) and Flemish (A21G) mutant amyloid beta proteins to human cerebral microvessel and aortic smooth muscle cells. Stroke. 2000 Feb;31(2):534-8.
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- Suo Z, Wu M, Citron BA, Wong GT, Festoff BW. Abnormality of G-protein-coupled receptor kinases at prodromal and early stages of Alzheimer's disease: an association with early beta-amyloid accumulation. J Neurosci. 2004 Mar 31;24(13):3444-52. PubMed.