22 September 2006. This week, details of findings Alzforum previously reported from meetings in St. Moritz, Switzerland, and Madrid, Spain, are published. In yesterday’s Sciencexpress online, Christian Haass, University of Munich, Germany, and colleagues in Europe and the U.S. reported on the physiological role for the β-secretase BACE1. In today’s Science, Mathias Jucker, University of Tubingen, Germany, also with European and U.S.-based collaborators, describes how formation of β-amyloid may be seeded by exogenous Aβ. While there is no indication that Aβ can be infectious, this work emphasizes the similarities between prion amyloids and those caused by non-infectious proteins.
Finding a physiological role for BACE1 has been on the front burner since BACE knockout mice were found to have variable and sometimes subtle phenotypes. When Haass’ group found that BACE expression was elevated in 2-week-old mouse pups but almost nonexistent in adult mice, they started to search for a developmental role for the secretase. That led to the discovery that BACE is intimately involved in the myelination of peripheral motoneurons. They found that absence of BACE leads to the accumulation of neuregulin 1 (NRG1), a BACE substrate and activator of ErbB receptors on myelinating Schwann cells. In the BACE-negative mice, peripheral motoneuron axons are hypomyelinated, despite a normal myelin ultrastructure. Whether BACE cleavage of NRG1 is critical in CNS myelination events is unclear, but first author Michael Willem and colleagues report that in BACE-/- mice, unprocessed NRG1 also accumulates in the brain. See earlier ARF meeting report for more in-depth coverage.
BACE is also responsible for the first of two proteolytic cleavages that release amyloid-β (Aβ) from its precursor protein. Once free in solution, Aβ can go on to form dimers, oligomers, protofibrils, and eventually amyloid plaques. How and why this process progresses faster in some brains is unclear, but the process can be “seeded,” much like a tiny crystal can nucleate the growth of a larger one from a solution. But as Matthias Jucker and colleagues report, the type of Aβ “crystals” that form depends very much on the nature of the seed and the material seeded.
First author Melanie Meyer-Luehmann and colleagues report that extracts from postmortem AD brains or old transgenic APP23 or APP/PS1 mice can seed Aβ deposition in mice that would not normally show signs of Aβ accumulation until they were older. But the nature of the deposits depends on the host/donor relationship. Extracts from APP/PS1 transgenic mice produce coarse, punctate Aβ deposits in APP23 hosts, whereas APP23 extracts yielded more diffuse deposits (quantitatively, the induction of deposits was similar in each case). The phenotypes seem to be based on the relative amounts of Aβ1-40 and Aβ1-42 produced in the donors and hosts, supporting the idea of different “strains” of Aβ, akin to the different prion protein strains that have been described. For more on this story, see our original meeting report.—Tom Fagan.
Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, DeStrooper B, Saftig P, Birchmeier C, Haass C. Control of peripheral nerve myelination and the beta-secretase BACE1. Science Express. 21 September, 2006. Abstract
Meyer-Luehmann M, Coomaraswamy J, Bolmont T, Kaeser S, Schaefer C, Kilger E, Neuenschwander A, Abramowski D, Frey P, Jaton AL, Vigouret J-M, Paganetti P, Walsh DM, Mathews PM, Ghiso J, Staufenbiel M, Walker LC, Jucker M. Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science. 22 September, 2006;313:1781-1784. Abstract