Kim S, Sato Y, Mohan PS, Peterhoff C, Pensalfini A, Rigoglioso A, Jiang Y, Nixon RA. Evidence that the rab5 effector APPL1 mediates APP-βCTF-induced dysfunction of endosomes in Down syndrome and Alzheimer's disease. Mol Psychiatry. 2015 Jul 21; PubMed.

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  1. This is an interesting paper, which follows up on an earlier paper in PNAS in 2010 from the same group. Randy has been following the endocytic connection in AD for many years and has published very well on the topic. The paper provides additional evidence for a selective role of the β-CTF of APP (C99). We long thought that β-CTF may have an "unspecific" neurotoxic function when it accumulates, but this paper shows a specific mechanism, namely the recruitment of APPL1 and the activation of Rab5, two endocytic proteins. Thus, when we speak about roles of APP and its fragments, we should not only speak about full-length APP and Aβ, but also about β-CTF. A recent study from Bart De Strooper’s lab (Barao et al., Cell Reports, in press) demonstrates that the β-CTF of another protein, the BACE1 substrate CHL1, is required for growth cone collapse in thalamic neurons. Together these studies raise the intriguing possibility that—more generally—β-CTFs may not just be fragments on the path of membrane protein degradation, but may have specific physiological roles.

    APPL1 should not be confused with the APP homolog APLP1, which is an unrelated protein. The APPL1 knock-down and rescue experiments are very convincing, in particular in the DS fibroblasts. Future experiments should further investigate the direct interaction between β-CTF and APPL1 when both proteins are expressed under endogenous conditions (and not just overexpressed as done here), although this may be technically challenging. Additionally, knockdown/knockout experiments in AD models, including AD mice, may be very helpful to further demonstrate a role for β-CTF not only in DS, but also in AD.   

    View all comments by Stefan Lichtenthaler

  2. I found this paper both convincing and very interesting because: 1) The in vitro results provide a specific mechanism for an APP-dependent but Aβ-independent toxicity pathway via β-CTF recruitment of Rab5 and APPL1 to the endosomal\lysosomal system. 2) This APPL1 pathway is upstream from NF-κB activation in neurons and potentially also in glia with many downstream consequences. 3) γ-Secretase inhibition increased β-CTF and made endosomal/lysosomal pathology worse, which suggests this pathway might help explain some of the adverse effects of γ-secretase inhibition. 4) The authors show increases in β-CTF and APPL1 in AD and the APPLI co-localizes with Rab5—arguing that this pathway is activated in AD.

    This is a novel mechanism and potentially very important. While it is difficult to predict the net contribution of this new pathway to other AD pathologies and symptoms, it seems likely to play some significant role and it offers new therapeutic targets. In addition, the potential correction of this new independent role for β-CTF in causing endosomal pathology is another reason we can hope BACE inhibitors may have some therapeutic benefits that are not shared by γ-secretase inhibitors or most Aβ immunotherapy approaches.

    Incidentally, the curry spice component curcumin is an NF-κB inhibitor. Since we have developed and been pursuing a more bioavailable form of curcumin for clinical trials with AD, we have encountered a community of parents of children with Down’s syndrome who have been treating their children with curcumin and blogging about improvements in their symptoms. Similar anecdotal reports suggest possible benefits in AD. Therefore, it is intriguing to see this new pathway as an upstream activator of NF-κB in AD and DS.    

    View all comments by Gregory Cole

  3. The paper is an elegant piece of work demonstrating, for the first time, the molecular basis of how b-CTF could play a role in the activation of Rab5, a process that is intricately associated with the enlargement of endosomes. Apart from the plaques and tangles, endocytic abnormalities are also cardinal features of AD. Nixon and co-workers now conclusively demonstrate that b-CTF binds to the Rab5 effector, APPL1, and thereby affects the activation of Rab5. This is, to my best of the knowledge, the first time, a molecular mechanism that links APP processing and enlargement of the endosomes has been identified and hence I am very enthusiastic about this work. Back in 2006 we identified Rab5/EEA-1 positive vesicles as involved in BACE1-mediated cleavage of APP (Rajendran et al., 2006). Now, this work connects another effector of Rab5 with APP processing and provides novel insight into how APP processing could be coupled with enlargement of early endosomes. In unpublished work from my lab, we have evidence that silencing of APPL1 reduces Ab levels, thereby providing additional support to the Nixon lab findings on APPL and AD. Overall, an excellent paper on the cell biology and biochemistry of AD.

    References:

    Rajendran L, Honsho M, Zahn TR, Keller P, Geiger KD, Verkade P, Simons K. Alzheimer's disease beta-amyloid peptides are released in association with exosomes. Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11172-7. PubMed.

    View all comments by Lawrence Rajendran

  4. There are a number of observations in AD research that are controversial or conflicting. However, one consistent observation agreed upon by all is that increased β-secretase processing of APP leads to increased risk for developing AD (brought about by multiple mechanisms: increased BACE activity during aging, mutations that make APP a better BACE substrate, increased APP gene copy number, etc.). Similarly, the “protective” mutation in APP (Jonsson et al., 2012) seems to make APP resistant to BACE cleavage (Maloney et al., 2014). This knowledge has been interpreted almost exclusively through the amyloid lens, since increased BACE processing also leads to increased amyloid-β (Aβ) levels.

    However, there is growing evidence that that not all deleterious effects of increased BACE processing of APP are mediated by Aβ, and this study further confirms that notion. In this study, the group from Nathan Klein Institute presents strong data that increased levels of APP β-CTF, and not that of Aβ, cause endosomal abnormalities via APPL1 and rab5. Here they characterize this interaction at molecular level and identify APP-CTF residues involved in binding APPL1. Together with the several earlier papers from Nixon and colleagues, this study leaves no doubt that β-CTF of APP mediates deleterious effects independent of Aβ.

    It is likely that increased BACE processing of APP could pose a double whammy. First, increased β-CTF levels by themselves bring about the toxic events described here. Second, γ-secretase processing of β-CTF would generate Aβ and APP Intracellular domain (AICD), which in turn causes deleterious events in vivo (tau pathology, memory impairment, neurodegeneration) independent of Aβ (Ghosal et al., 2009). Protein structure studies suggest that β-CTF is a better substrate for γ-secretase cleavage (Tian et al., 2010) and several groups have independently shown that β-CTF generates increased AICD signaling (Goodger et al., 2009; Belayaev et al., 2010; Flammang et al., 2012).

    In any case, data that BACE processing of APP brings about AD-related deleterious effects independent of Aβ are becoming so compelling that one cannot ignore their implications for drug development. There is growing evidence that it may be unrealistic to expect that targeting Aβ alone will be effective against AD, even if the anti-amyloid treatment is started very early during disease progression.

    References:

    Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, Stefansson H, Sulem P, Gudbjartsson D, Maloney J, Hoyte K, Gustafson A, Liu Y, Lu Y, Bhangale T, Graham RR, Huttenlocher J, Bjornsdottir G, Andreassen OA, Jönsson EG, Palotie A, Behrens TW, Magnusson OT, Kong A, Thorsteinsdottir U, Watts RJ, Stefansson K. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature. 2012 Aug 2;488(7409):96-9. PubMed.

    Maloney JA, Bainbridge T, Gustafson A, Zhang S, Kyauk R, Steiner P, van der Brug M, Liu Y, Ernst JA, Watts RJ, Atwal JK. Molecular mechanisms of Alzheimer disease protection by the A673T allele of amyloid precursor protein. J Biol Chem. 2014 Nov 7;289(45):30990-1000. Epub 2014 Sep 24 PubMed.

    Ghosal K, Vogt DL, Liang M, Shen Y, Lamb BT, Pimplikar SW. Alzheimer's disease-like pathological features in transgenic mice expressing the APP intracellular domain. Proc Natl Acad Sci U S A. 2009 Oct 27;106(43):18367-72. PubMed.

    Tian Y, Crump CJ, Li YM. Dual role of alpha-secretase cleavage in the regulation of gamma-secretase activity for amyloid production. J Biol Chem. 2010 Oct 15;285(42):32549-56. PubMed.

    Goodger ZV, Rajendran L, Trutzel A, Kohli BM, Nitsch RM, Konietzko U. Nuclear signaling by the APP intracellular domain occurs predominantly through the amyloidogenic processing pathway. J Cell Sci. 2009 Oct 15;122(Pt 20):3703-14. PubMed.

    Belyaev ND, Kellett KA, Beckett C, Makova NZ, Revett TJ, Nalivaeva NN, Hooper NM, Turner AJ. The transcriptionally active amyloid precursor protein (APP) intracellular domain is preferentially produced from the 695 isoform of APP in a {beta}-secretase-dependent pathway. J Biol Chem. 2010 Dec 31;285(53):41443-54. PubMed.

    Flammang B, Pardossi-Piquard R, Sevalle J, Debayle D, Dabert-Gay AS, Thévenet A, Lauritzen I, Checler F. Evidence that the Amyloid-β Protein Precursor Intracellular Domain, AICD, Derives From β-Secretase-Generated C-Terminal Fragment. J Alzheimers Dis. 2012 Jan 1;30(1):145-53. PubMed.

    View all comments by Sanjay Pimplikar

  5. Endocytic pathway abnormalities have long been implicated in excessive Aβ deposition in Alzheimer's disease (AD) and Down's syndrome (DS). In particular, both endocytosis and recycling have been shown to be persistently activated, with enlarged endosomes in the AD brain associated with increased recycling (rab4) and internalization (rab5) markers. Given the special importance of endocytosis in the processing of APP and the production of Aβ, this topic has been a matter of intense research and discussion over the years. Importantly, aberrations of membrane turnover in AD have been documented in both familial and sporadic cases, with rab5 upregulation being one of the earliest neuronal responses. Despite these important recent developments, the specific mechanisms underlying these processes and their implications for neuronal biology and neurodegeneration remain poorly defined.

    In this study, Kim et al., led by Ralph Nixon, address two important questions: Firstly, why is the endosomal regulator rab5 persistently activated in AD models? And secondly, how does enhanced endocytosis impact the biology and integrity of axons? Adaptor protein APPL1 and the β C-terminal fragment of APP (βCTF) are shown to be the key culprits! Indeed, excessive βCTF appears to recruit more APPL1 to the endocytic (rab5 positive) endosomes and through this causes persistent activation of GTP-rab5. This, in turn, ramps up endocytosis, leading to the production of oversized endosomes. While the functional significance of enhanced endocytosis under elevated βCTF remains unclear, Kim et al. present convincing data for its strong pathological impact: Larger endosomes pose a major challenge to the axonal transport system, causing traffic jams, swelling, and dystrophies. Whether and to what extent these processes contribute to the pathobiology of sporadic AD remains to be established.

    View all comments by Saak V. Ovsepian

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