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...
I recommend this paper
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...