Lee EB, Zhang B, Liu K, Greenbaum EA, Doms RW, Trojanowski JQ, Lee VM. BACE overexpression alters the subcellular processing of APP and inhibits Abeta deposition in vivo. J Cell Biol. 2005 Jan 17;168(2):291-302. PubMed.
Recommends
Please login to recommend the paper.
Comments
Lund University
EB Lee and colleagues provide very interesting data indicating that high BACE overexpression paradoxically reduces Aβ levels and plaque pathology in Tg2576 transgenic mice harboring the APP Swedish mutation. They employ diverse methods to demonstrate that BACE overexpression reduces transport of mature and phosphorylated APP into axons. This publication underscores the importance of studying AD biology in neurons, especially their processes. Increasing evidence is placing the critical site of Aβ generation, and accumulation, within neurites and synapses. Disruption of the perforant path has previously been shown to reduce plaque pathology in synaptic terminal fields of the hippocampus. Aβ …More
A topic not discussed in the paper is the growing literature on intraneuronal Aβ
accumulation with AD pathogenesis. Indeed, the labs of Virginia Lee
and John Trojanowski were pioneers in studies on intracellular Aβ.
Their work raises the intriguing question of why the low BACE
expressing APP mutant mice have reduced plaques in hippocampus but
increased plaques in cortex. The authors speculate that differential
effects of increased BACE in projection neurons with long axons
compared to smaller interneurons with shorter axons may be involved.
Despite the emphasis on axons and presynaptic compartments, one could
also consider the potential involvement of dendrites and postsynaptic
compartments, which are more difficult to study but also accumulate
Aβ. Overall, this is exciting new work using rigorous analysis of
APP/Aβ processing with elegant in vivo experiments that provide
novel insights into the neurobiology of AD.
Yale University School of Medicine
I agree with Martin and Gouras that this paper deserves serious study since it is an ambitious attempt to explore whether cleavage of APP at different subcellular sites determines whether Abeta peptides are ultimately toxic to the neurons in which the are produced.
The authors found that increased expression of beta secretase in mice has a paradoxical effect on Aβ levels and plaque development. High levels of beta secretase decrease Aβ levels and retard plaque formation, contrary to what might have been predicted. They propose that excessive beta secretase cleaves APP prematurely in the ER/Golgi regions of neurons, thereby reducing their translocation to distal segments where it is …More
Other interesting effects are also described, such as a striking decrease in levels of phosphorylated C99, a product of beta cleavage, while non-phosphorylated C99 and other amino terminal fragments of APP accumulate inside cells. This makes one wonder whether high levels of beta secretase, or the peptides they generate, have as yet unsuspected actions that might influence other metabolic pathways including kinase/phosphatase actions and the PS1/gamma secretase complex.
Make a Comment
To make a comment you must login or register.