. An aberrant sugar modification of BACE1 blocks its lysosomal targeting in Alzheimer's disease. EMBO Mol Med. 2015 Jan 15;7(2):175-89. PubMed.


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  1. BACE1 stands as a very attractive therapeutic target for AD. However, with the identification of physiologically relevant BACE1 substrates, one should be aware that a complete block of BACE1 activity may lead to unintended side effects similar to what was seen with the γ-secretase inhibition studies, e.g., Semagacestat. Therefore, the discovery of alternative strategies to target these secretases are of high value.

    The identification of this novel sugar modification of BACE1 that seems particularly increased in Alzheimer’s disease brain highlights once more the complexity of the processes going on during AD progression, and again calls for caution when rushing toward a new, poorly understood therapeutic approach.

    The authors show that GnT-III, the enzyme responsible for the bisecting GlcNAc modification, is upregulated in the brains of AD patients, and suggest that this modification promotes AD pathogenesis by delaying BACE1 degradation. Although the authors claim that the bisecting GlcNAc blocks the lysosomal trafficking of BACE1 in the mouse brain, the difference in co-localization with the late endosome/lysosome marker Lamp1 is very small between the GnT-III-positive and –negative genotypes (~5 percent increase in the latter), which makes this argument rather weak. Nevertheless, it is clear that the bisecting GlcNAc modification modulates BACE1 levels and APP processing. Interestingly, the authors show that the inhibition of GnT-III inhibits only the processing of APP by BACE1, not the processing of the other substrates.

    Since the GnT-III knockout mice do not present any obvious phenotypes, the authors emphasize the possibility of a new AD therapy by targeting this glycosyltransferase. Although very little is known about GlcNAc modification function, GlcNAc is highly expressed in the normal brain and it has been shown to suppress cancer metastasis. This evidence suggests that GlcNAc might play an important physiological role, and therefore the absence of a phenotype does not imply absence of risk for mechanistic side effects when blocking the enzyme. We should not forget that BACE1 knockout mice were also initially considered to be normal and throughout the years many complex phenotypes have been revealed.

    Nevertheless, the discovery of this aberrant sugar modification is highly interesting and might inspire some researchers to look for alternative therapeutic strategies.

  2. This study described a novel observation that BACE1 stability can be regulated through bisecting N-acetylglucosamine. The authors showed that BACE1 normally undergoes bisecting N-acetylglucosamine by glycosyltransferase GnT-III (encoded by the MGAT3 gene). Interestingly, MGAT3 levels were higher in AD patients, even noticeably higher in early AD patients’ brains than in non-demented controls. Consequently, more BACE1 was modified by MGAT3 as evidenced by the slightly slower migration on the SDS gel. When BACE1 is modified through bisecting N-acetylglucosamine, its stability is enhanced due to less trafficking to late endosomes/lysosomes for degradation. Their mouse genetic studies showed that mice lacking the MGAT3 gene decreased BACE1 stability by directing more BACE1 to the lysosome, and had a reduction in Aβ generation. This observation is important because inhibition of MGAT3 activity likely reduces amyloid deposition indirectly.

    One unsolved physiological question is, why does MGAT3 target BACE1, but not APP, or other BACE1 substrates? It is known that cellular trafficking of BACE1 and APP are regulated by different pathways, although both are type I transmembrane proteins. Trafficking of BACE1 is also controlled by RTN3, and mice deficient in RTN3 show increased stability of BACE11. RTN3 interacts only with BACE1, not APP (see Shi et al., 2014). 


    . Impact of RTN3 deficiency on expression of BACE1 and amyloid deposition. J Neurosci. 2014 Oct 15;34(42):13954-62. PubMed.

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  1. Scientists Suggest Curbing Sugar Modification to Tame BACE