De Strooper and colleagues report that knocking out the B/C isoforms of Aph1, a crucial component of the γ-secretase complex, protects a double transgenic mouse model of AD (APP/PS1) against learning and memory deficits. The work suggests that the Aph1A isoform is the one that contributes most to amyloidogenic processing of APP. The Aph1B/C deficient mice also have a much lower Aβ burden in the brain. Joint first authors Lutgarde Serneels and Jérôme Van Biervliet and colleagues also found that Aph1B- or Aph1C-containing γ-secretases churn out proportionately longer Aβ peptides than do Aph1A containing proteases and also have a different structural conformation. Notch processing in Aph1B/C-deficient animals also appears normal. “Since the Aph1B γ-secretase complex is present and active in the human brain, the selective inhibition of this complex has the potential to translate into an approach to lower Aβ peptide production in human AD with relatively few side effects,” write the authors.

In the JBC paper, Diamond and colleagues report that extracellular aggregates of tau are taken up by cultured cells and can seed intracellular fibril formation. First author Bess Frost and colleagues also show that intracellular tau can transfer between cells in culture. “Our data indicate that tau aggregates can propagate a fibrillar, misfolded state from the outside to the inside of a cell,” write the authors. The work may open up a new appreciation of how tau pathologies spread in the brain. In AD, for example, “ghost,” or extracellular tau tangles, presumably left behind from dead or dying cells, could be silos for spreading aggregation seeds or templates among healthy cells. “Propagation via progressive, templated misfolding suggests a general pathogenic mechanism for other neurodegenerative diseases linked to amyloid protein aggregation,” suggest the authors.—Tom Fagan.

References:
Serneels L, Van Biervliet J, Craessaerts K, Dejaegere T, Horre K, Van Houtvin T, Esselmann H, Paul S, Schafer MK, Berezovska O, Hyman BT, Sprangers B, Sciot R, Moons L, Jucker M, Yang Z, May PC, Karran E, Wiltfang J, D’Hooge R, De Strooper B. gamma-secretase heterogeneity in the Aph1 subunit: Relevance for Alzheimer’s disease. Science. 2009, March 19, online. Abstract

Frost B, Jacks RL, Diamond MI. Propagation of tau misfolding from the outside to the inside of a cell. Journal of Biological Chemistry. 2009, March 11. Abstract