Ye X, Feng T, Tammineni P, Chang Q, Jeong YY, Margolis DJ, Cai H, Kusnecov A, Cai Q. Regulation of Synaptic Amyloid-β Generation through BACE1 Retrograde Transport in a Mouse Model of Alzheimer's Disease. J Neurosci. 2017 Mar 8;37(10):2639-2655. Epub 2017 Feb 3 PubMed.

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  1. The authors report very exciting findings on snapin overexpression being able to revert Aβ accumulation at synaptic terminals and concomitantly improve cognitive performance. I am particularly convinced by the impact of snapin overexpression on amyloid oligomerization in the AD mouse brain. However, I am less convinced about it being mediated by a rescue of BACE1 transport specifically mediated by snapin. I can envision an alternative and also compatible scenario, where APP would be co-transported in endosomes with BACE1 and the lack of retrograde transport could enhance APP processing distally. Or there may even be a more general rescue of axonal impairments previously described in AD (e.g., work from the Goldstein lab and others).

    Caution is also necessary when using CI-MPR as a marker of late endosomes, since MPR cycles between the trans-Golgi network and endosomes, both early and late, to a proportion variable depending on the cell type (Lin et al.,  2004). In neurons, the endosomal localization of MPR has not been characterized. It is also important to note that the early endosomal marker EEA1 is specific to dendrites (Wilson et al., 2000) and thus should not be used to characterize axonal endosomes. 

    References:

    Lin SX, Mallet WG, Huang AY, Maxfield FR. Endocytosed cation-independent mannose 6-phosphate receptor traffics via the endocytic recycling compartment en route to the trans-Golgi network and a subpopulation of late endosomes. Mol Biol Cell. 2004 Feb;15(2):721-33. Epub 2003 Oct 31 PubMed.

    Wilson JM, de Hoop M, Zorzi N, Toh BH, Dotti CG, Parton RG. EEA1, a tethering protein of the early sorting endosome, shows a polarized distribution in hippocampal neurons, epithelial cells, and fibroblasts. Mol Biol Cell. 2000 Aug;11(8):2657-71. PubMed.

    View all comments by Claudia Almeida

  2. This is very interesting work. Ye et al. provide strong evidence that approaches that aim to restore axonal trafficking and lysosomal degradation of BACE1 may represent a potential therapeutic target for AD. It has been known for many years that BACE1 accumulates in AD brains. Several mechanisms have been proposed for such accumulation but evidence is accumulating in support of post-translational mechanisms. Over a decade ago we reported that BACE1 is degraded in lysosomes. We proposed that impaired lysosomal degradation of BACE1 is a leading candidate mechanism underlying BACE1 elevation in AD. Our hypothesis was based on our findings showing that the depletion of the clathrin adaptor GGA3 results in BACE1 accumulation owing to impaired trafficking of BACE1 to lysosomes. In neurons, lysosomal degradation of axonal protein depends on their retrograde transport to the soma, where mature lysosomes reside. Ye et al. clearly showed that impairment of retrograde axonal transport of BACE1 leads to presynaptic accumulation of BACE1 and, as a consequence, increased Aβ production. More importantly, they showed that the overexpression of snapin was able to restore retrograde trafficking of BACE1, reduce synaptic levels of Aβ, and improve cognitive deficits in hAPP Tg mice. Most likely other trafficking molecules in addition to snapin play keys role in BACE1 axonal trafficking and degradation. Thus, more studies are needed on this important topic.

    View all comments by Giuseppina Tesco

  3. We thank our colleagues for taking the time to read our paper, and also appreciate their positive comments.

    Dr. Almeida’s points are well taken. As we discussed in the manuscript, the Roy lab elegantly showed that APP and BACE1 convergence and APP cleavage occur at presynaptic terminals, triggering amyloidogenesis (Das et al., 2013; Das et al., 2016). They demonstrated that APP and BACE1 are co-transported in axons and interact during this transit. Consistent with these findings, we showed the co-existence of APP and BACE1 in late endosomes that were purified from mouse brains (Ye and Cai, 2014). Our current study provides new lines of evidence that late endosome-loaded APP and BACE1 accumulate within presynaptic terminals of AD neurons. Thus, while we mainly focused on investigating retrograde transport of BACE1, it is likely that these late endosomes are also loaded with APP. Deficiency in snapin-mediated retrograde transport leads to retention of both APP and BACE1 within late endosomes in distal axons and at presynaptic terminals, enhancing β cleavage of APP. Remarkably, we detected the same phenotypes in mutant hAPP mice and snapin-KO mice: more severe accumulation of BACE1 within late endosomes and at presynaptic terminals. Our findings support the notion that defective retrograde transport causes the accumulation of both APP and BACE1 within late endosomes, thereby augmenting synaptic BACE1 processing of APP in AD neurons.

    With regard to Dr. Almeida’s comments on CI-MPR, it was originally shown to be a membrane protein preferentially located in late endosomes (Griffiths et al., 1988). We previously demonstrated that anti-CI-MPR-immunogold specifically labels the luminal vesicles of late endosomes in cortical neurons (Cai et al., 2010). Deleting snapin results in late endosomes clustered in the soma and processes of cortical neurons. In addition to CI-MPR, we alternatively examined the other marker of late endosomes—Rab7. Consistently, we found that BACE1 is retained within Rab7-associated late endosomes at presynaptic terminals of mutant hAPP Tg mice and in AD patient brains. Moreover, a significant portion of BACE1 co-localized and co-migrated with Rab7-labeled late endosomes along the same axon, with a biased long-distance retrograde transport toward the soma of neurons. Retrograde transport of BACE1-loaded late endosomes is impaired in AD axons. Our results are also consistent with previous studies from the Gouras lab showing that late endosomes/MVBs enriched with APP and Aβ42 accumulate in distal axons and synaptic compartments of vulnerable AD neurons (Takahashi et al., 2002; Takahashi et al., 2004; Gouras et al., 2005), suggesting that defects in retrograde transport results in enhanced BACE1 cleavage of APP within late endosomes.

    In our study, we did not use EEA1 as a marker to label axonal endosomes. As Dr. Almeida pointed out, early endosomal marker EEA1 is specific to dendrites. We found that EEA1 is absent from presynaptic terminals, which excludes the possibility of BACE1 retention within EEA1-associated early endosomes in the axon of AD neurons.

    References:

    Cai Q, Lu L, Tian JH, Zhu YB, Qiao H, Sheng ZH. Snapin-regulated late endosomal transport is critical for efficient autophagy-lysosomal function in neurons. Neuron. 2010 Oct 6;68(1):73-86. PubMed.

    Das U, Scott DA, Ganguly A, Koo EH, Tang Y, Roy S. Activity-Induced Convergence of APP and BACE-1 in Acidic Microdomains via an Endocytosis-Dependent Pathway. Neuron. 2013 Aug 7;79(3):447-60. PubMed.

    Das U, Wang L, Ganguly A, Saikia JM, Wagner SL, Koo EH, Roy S. Visualizing APP and BACE-1 approximation in neurons yields insight into the amyloidogenic pathway. Nat Neurosci. 2016 Jan;19(1):55-64. Epub 2015 Dec 7 PubMed.

    Gouras GK, Almeida CG, Takahashi RH. Intraneuronal Abeta accumulation and origin of plaques in Alzheimer's disease. Neurobiol Aging. 2005 Oct;26(9):1235-44. PubMed.

    Griffiths G, Hoflack B, Simons K, Mellman I, Kornfeld S. The mannose 6-phosphate receptor and the biogenesis of lysosomes. Cell. 1988 Feb 12;52(3):329-41. PubMed.

    Takahashi RH, Milner TA, Li F, Nam EE, Edgar MA, Yamaguchi H, Beal MF, Xu H, Greengard P, Gouras GK. Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am J Pathol. 2002 Nov;161(5):1869-79. PubMed.

    Takahashi RH, Almeida CG, Kearney PF, Yu F, Lin MT, Milner TA, Gouras GK. Oligomerization of Alzheimer's beta-amyloid within processes and synapses of cultured neurons and brain. J Neurosci. 2004 Apr 7;24(14):3592-9. PubMed.

    Ye X, Cai Q. Snapin-mediated BACE1 retrograde transport is essential for its degradation in lysosomes and regulation of APP processing in neurons. Cell Rep. 2014 Jan 16;6(1):24-31. Epub 2013 Dec 27 PubMed.

    View all comments by Qian Cai

  4. This study provides interesting new insights into the possible disease relevance of the accumulation of endolysosomal organelles within the dystropic axons that surround amyloid plaques. In a parallel effort, my group has recently identified a distinct JIP3-dependent mechanism that is critical for the axonal transport and maturation of lysosomes and that perturbation of this pathway also results in enhanced APP processing and dramatically worsened amyloid plaque pathology (Gowrishankar et al, 2017).

    Thus, while it has long been known that autophagosomes, lysosomes and hybrids thereof robustly accumulate within the swollen axons around amyloid plaques (Terry et al, 1964; Nixon et al, 2005) and furthermore that such organelles contain enzymes that mediate APP processing (Kandalepas et al, 2013; Yu et al, 2004), new tools to selectively manipulate the axonal transport of such organelles are finally providing evidence that the abnormal axonal accumulation of endolysosomes is of Alzheimer's disease disease relevance.

    Gowrishankar S, Wu Y, Ferguson SM
    Impaired JIP3-dependent axonal lysosome transport promotes amyloid plaque pathology.
    J Cell Biol. 2017 Aug 7; PubMed: 28784610

    Kandalepas, P.C., K.R. Sadleir, W.A. Eimer, J. Zhao, D.A. Nicholson, and R. Vassar. 2013. The Alzheimer's beta-secretase BACE1 localizes to normal presynaptic terminals and to dystrophic presynaptic terminals surrounding amyloid plaques. Acta Neuropathol. 126:329-352.

    Nixon, R.A., J. Wegiel, A. Kumar, W.H. Yu, C. Peterhoff, A. Cataldo, and A.M. Cuervo. 2005. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. Journal of neuropathology and experimental neurology. 64:113-122.

    Terry, R.D., N.K. Gonatas, and M. Weiss. 1964. Ultrastructural Studies in Alzheimer's Presenile Dementia. Am J Pathol. 44:269-297.

    Yu WH, Kumar A, Peterhoff C, Shapiro Kulnane L, Uchiyama Y, Lamb BT, Cuervo AM, Nixon RA. Autophagic vacuoles are enriched in amyloid precursor protein-secretase activities: implications for beta-amyloid peptide over-production and localization in Alzheimer's disease. The international journal of biochemistry & cell biology. 2004;36(12):2531-40. doi: 10.1016/j.biocel.2004.05.010. PMID: 15325590.

    View all comments by Shawn Ferguson

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