19 April 2006. Donald Price, Johns Hopkins University, Baltimore, presented results of BACE knockout mouse studies. By filter trap and immunostaining methods, he showed that the BACE-/- mouse had no Aβ plaques in the brain. The knockout mouse also exhibited alterations in behavior, as monitored by the Morris water maze and the radial water maze. But the mice exhibited no developmental abnormalities or adult onset neuropathology. Interestingly, memory deficits, but not emotional and cognitive deficits, in APPswe/PS1ΔE9 mice could be rescued by BACE deletion. Finally, as a potential therapeutic intervention, he introduced a Tet-off conditional expression system coupled to lentiviral RNAi injection strategies for attenuating BACE and demonstrated successful clearance of plaques at the injected site of APPswe/PS1ΔE9 mouse brain.

Jordan Tang, Oklahoma Medical Research Foundation, Oklahoma City, elaborated on a mechanism of internalization and recycling of BACE, otherwise known as memapsin2 (M2) and APP, and the binding proteins responsible for their transport. By pull-down experiment and immunoprecipitation assay, he demonstrated that APP formed a complex with ApoER2 and the APP adapter molecules X11α and X11β. Tang also provided evidence that ApoER2 mediates Aβ production. If ApoER2 was overexpressed, alone, in N2a-APPswe cells, Aβ secretion was reduced. However, if ApoER2 was expressed in the presence of ApoE or very low-density lipoprotein (VLDL) in N2a-APPswe cells, Aβ secretion was enhanced. This led to the suggestion that a protein complex of ApoE, ApoER2, X11, and APP undergoes endocytosis to endosomes and enhances Aβ production (see ARF related news story).

Edward Lee, Hospital of the University of Pennsylvania, presented the paradoxical finding of inhibition of amyloid deposition following greater than a sevenfold overexpression of BACE in transgenic mice. Using biochemical markers for APP maturation, he demonstrated that BACE overexpression led to decreased axonal transport of APP and consequent depletion of synaptic Aβ in APP x BACE transgenic mouse, in vivo phospho-APP labeling, and sciatic nerve ligations. By use of a microdialysis system, he also showed that Aβ1-40 in the hippocampal interstitial fluid of the APP x BACE transgenic mouse was reduced as compared to the APP transgenic mouse. The axonal depletion of APP by BACE overexpression was not coupled with changes in other transport proteins, for example, kinesin. Finally, Lee raised the question of whether increased BACE activity might increase APP turnover in the cytosol, leading to less axonal transport and less secretion of Aβ at synapses. In the short talk slated for this session, Michael Willem, Adolf-Butenandt-Institute, Munich, Germany, presented evidence that BACE expression is high early in postnatal CNS. He then showed that sensory neurons of BACE1-deficient mice are hypomyelinated. Willem elucidated that the poorly ensheathed neurons resulted from changes in type 3 neuregulin-1 (NRG-1) cleavage. He pointed out that therapeutic strategies for AD using BACE inhibitors or γ-secretase inhibitors might interfere with NRG-1 function, since NRG-1 is a substrate for both secretases (see ARF related news story).