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 at synapses may even have a physiological role that as yet is poorly defined. A central but more controversial issue is how Aβ generation at synapses links to synaptic dysfunction and plaque formation. 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...  Read more

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 at synapses may even have a physiological role that as yet is poorly defined. A central but more controversial issue is how Aβ generation at synapses links to synaptic dysfunction and plaque formation. 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.

View all comments by Gunnar K. Gouras

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 presumed that abeta peptides might be more toxic. While this is an interesting idea, I would look for deeper explanations.

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...  Read more

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 presumed that abeta peptides might be more toxic. While this is an interesting idea, I would look for deeper explanations.

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.

View all comments by Vincent Marchesi