. A seed for Alzheimer amyloid in the brain. J Neurosci. 2004 May 19;24(20):4894-902. PubMed.


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  1. In search of the “β Bang”

    The evidence strongly favors a crucial role of the peptide Aβ in the pathogenesis of Alzheimer’s disease (AD). In vitro studies have nicely illuminated the mechanics of polymerization and fibrillization of Aβ and other proteopathic molecules, and the aggregation process has been shown to be strongly influenced by protein concentration. In vivo, Aβ deposition can be accelerated by increased Aβ production, for example, in familial (genetic) AD, Down’s syndrome, in AβPP-overexpressing mice, or following head injury. In many cases of AD, however, a genetic or environmental contribution is not apparent, and in no instance has the actual prime mover of protein polymerization in vivo been identified. Furthermore, the global levels of Aβ in normal brain are well below those needed to achieve the critical polymerization threshold that is seen in vitro. This impediment to aggregation might be overcome by a focal accrual of protein (such as in membranes and/or organelles) or by the action of pathological chaperone molecules that promote Aβ aggregation.

    Hayashi and colleagues propose that one such cofactor could be GM1 ganglioside, which, when bound to Aβ (GAβ), alters the conformation of Aβ and acts as a seed for aggregation. Their studies show that GM1 accelerates the fibrillization of soluble, seed-free Aβ in vitro, and increases the cytotoxicity of Aβ40 in rat primary neuronal cultures. An antibody to GAβ inhibited amyloid fibril formation in vitro, and immuno-electron microscopy indicates that GAβ is localized selectively to the ends of Aβ40 fibrils, whereas antibody 4G8 (to amino acids 17-24 of Aβ) labels only the sides of the fibrils.

    While many issues remain to be resolved, the results are a useful step in the search for the prime mover of Aβ polymerization in the aging brain (the identify of what one might call, with apologies to astronomers, the “β-Bang”). Ultimately, in vivo studies will be needed to confirm or reject competing theories of initial pathogenesis. In this regard, cortical extracts from AD brains and AβPP-transgenic mice have been shown to seed (i.e., “stimulate the growth or development of”) senile plaques and cerebral amyloid angiopathy in young, AβPP-transgenic mice (see Gabrielle Strobel’s summary of Mathias Jucker’s presentation at the St. Moritz meeting in ARF related news story). Selective removal of Aβ from the extracts significantly diminishes the seeding effect, implicating the peptide in the phenomenon. However, synthetic Aβ so far has failed to comparably induce amyloidogenesis in transgenic mice. If a specific cofactor is needed to properly seed Aβ deposition in brain, and if GM1 ganglioside is that cofactor, then injection of GAβ into the brains of AβPP-transgenic mice should yield a phenotype similar to that generated by diseased brain extracts.

    Finally, it is worth mentioning that GM1 ganglioside is a naturally occurring component of the cell membrane that is an important player in, among other things, the development, growth, and repair of neurons. Preliminary clinical studies suggest that peripheral administration of GM1 ganglioside may benefit patients with Parkinson’s disease (Schneider et al., 1998), and it has even been delivered intracerebrally into a small number of AD patients (Svennerholm et al., 2002). While the latter, limited trial suggests some benefit in the short term, the findings of Hayashi and colleagues caution that a better understanding of the interactions of GM1 ganglioside and Aβ is warranted to insure the safety and long-term efficacy of such procedures.