This is an interesting study by Wu and colleagues. Arc appears to mediate PS1 trafficking through the endosomal pathway which increases γ-secretase cleavage of APP and increases Aβ generation. It will be important to determine where and how Arc is altering PS1 localization. Aβ secretion appears to occur both from axons and dendrites (Wei et al., 2011; Cirrito et al., 2005), though Arc is only found dendritically. Based on Fig 1A and B in this paper, Arc knockouts completely blocked the effect of increased synaptic activity on Aβ levels in brain extracts. It will be important to determine if and how Arc is affecting axonal Aβ generation.

References:
Wei W, Nguyen LN, Kessels HW, Hagiwara H, Sisodia S, Malinow R. Amyloid beta from axons and dendrites reduces local spine number and plasticity. Nat Neurosci. 2010 Feb;13(2):190-6. Abstract

Cirrito JR, Yamada KA, Finn MB, Sloviter RS, Bales KR, May PC, Schoepp DD, Paul SM, Mennerick S, Holtzman DM. Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron. 2005 Dec 22;48(6):913-22. Abstract

View all comments by John Cirrito

This elegant study identifies Arc as a presenilin-1 (PS1) interacting protein that links synaptic activity with γ-secretase processing of APP in neurons. Detailed analysis of subcellular localization of APP, PS1, and Arc by immunofluorescence and immunoelectron microscopy methods suggest a mechanism whereby Arc facilitates association of PS1 with endosomes that contain internalized APP. Thus, it appears that the subset of APP that contributes to activity-dependent Aβ production encounters PS1 in endocytic organelles in dendrites of excitatory neurons.

Arc is known to associate with endophilin-2/3 and dynamin on endosomes, and mediate AMPA receptor (AMPAR) endocytosis. Whereas the last is markedly reduced in Arc knockout neurons, this does not appear to be the case with PS1 or APP. Whether this indicates Arc regulation of PS1/APP colocalization in tubulovesicular endosomes is distinct from its function in regulating the endocytic machinery responsible for AMPAR endocytosis remains to be investigated.

View all comments by Gopal Thinakaran