Morel E, Chamoun Z, Lasiecka ZM, Chan RB, Williamson RL, Vetanovetz C, Dall'armi C, Simoes S, Point Du Jour KS, McCabe BD, Small SA, Di Paolo G. Phosphatidylinositol-3-phosphate regulates sorting and processing of amyloid precursor protein through the endosomal system. Nat Commun. 2013;4:2250. PubMed.
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University of Zurich
This is a spectacular study, linking lipid metabolism, membrane trafficking and Alzheimer's disease. It is carefully done, combining elegant cell biology in neurons with biochemistry. For me, the most important aspect of the study is that the findings suggest that in the absence of any genetic abnormalities in the retromer components, misregulation in lipid levels could phenocopy late-onset AD symptoms.
The role of endocytosis in the generation of Aβ peptides was identified long ago (Koo et al., 1994;. Cataldo et al., , 1997(). We previously showed that Rab5-EEA1 positive endosomes are involved in the beta-secretase processing of APP (Rajendran et al., 2006; Rajendran et al., 2008). Wim Annaert's lab demonstrated that BACE1 traffics to the early endosomes via a Arf6 mediated pathway (Sannerud et al., 2011) and we showed in an earlier work that APP endocytosis depends on cholesterol and flotillin (Schneider et al., 2008). These studies established sorting of both APP and BACE1 to early endosomes as key events in the generation of Aβ. Now, the authors looked carefully at the role of endosomal lipids, such as phophatidylinositol-3-phosphate lipids, in the sorting of APP. They demonstrate that PI3P deficiency, as observed in AD brains and in the brains of APP transgenic mice, leads to enhanced amyloidogenic processing of APP. They attribute this to altered sorting of APP.
The authors show that APP can be sorted to the intraluminal vesicles (ILVs) of multivesicular bodies (MVBs)- a process whereby membrane proteins are either marked for degradation via lysosomes or for the removal by secretion through exosomes. They show that APP, if ubiquitinated, can be sorted to these ILVs as a means for their removal from early endosomes, where they are processed by BACE1. Misregulation of this sorting to ILVs, due to PI3P deficiency or mutation in ubiquitination signals, leads to enhanced Aβ secretion, thus linking ILV sorting of APP to downregulation of amyloidogenic processing of the protein. Since PI3P levels are decreased in late-onset AD cases, this work offers a convincing explanation for the increased Aβ levels in AD. Interestingly, early work by Anne Cataldo and Ralph Nixon has shown that the early endosomes are enlarged in AD patient brains and the current work lends supportive evidence that PI3P deficiency could contribute to this abnormal morphology and decreased ILV sorting of APP.
Of note, since the authors discover that APP is sorted to the intra-luminal vesicles (ILVs) of the multivesicular endosomes, it would be interesting to see if some of the APP is secreted via exosomes (the vesicles that are derived from the fusion of MVBs with the plasma membrane thereby releasing their ILVs as exosomes). Since Aβ has been shown to be released via exosomes (Rajendran et al., 2006), it would be interesting to see if the precursor protein is secreted via exosomes as well. Of course, an open question is what happens to beta and gamma-secretase sorting under these conditions? Interesting times ahead for more cell biology studies in AD.
Koo EH, Squazzo SL. Evidence that production and release of amyloid beta-protein involves the endocytic pathway. J Biol Chem. 1994 Jul 1;269(26):17386-9. PubMed.
Cataldo AM, Barnett JL, Pieroni C, Nixon RA. Increased neuronal endocytosis and protease delivery to early endosomes in sporadic Alzheimer's disease: neuropathologic evidence for a mechanism of increased beta-amyloidogenesis. J Neurosci. 1997 Aug 15;17(16):6142-51. PubMed.
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.
Rajendran L, Schneider A, Schlechtingen G, Weidlich S, Ries J, Braxmeier T, Schwille P, Schulz JB, Schroeder C, Simons M, Jennings G, Knölker HJ, Simons K. Efficient inhibition of the Alzheimer's disease beta-secretase by membrane targeting. Science. 2008 Apr 25;320(5875):520-3. PubMed.
Schneider A, Rajendran L, Honsho M, Gralle M, Donnert G, Wouters F, Hell SW, Simons M. Flotillin-dependent clustering of the amyloid precursor protein regulates its endocytosis and amyloidogenic processing in neurons. J Neurosci. 2008 Mar 12;28(11):2874-82. PubMed.
Sannerud R, Declerck I, Peric A, Raemaekers T, Menendez G, Zhou L, Veerle B, Coen K, Munck S, De Strooper B, Schiavo G, Annaert W. ADP ribosylation factor 6 (ARF6) controls amyloid precursor protein (APP) processing by mediating the endosomal sorting of BACE1. Proc Natl Acad Sci U S A. 2011 Aug 23;108(34):E559-68. PubMed.
University of Utah School of Medicine
The study by Das et al. was meticulously conducted and provides an important platform for further work in understanding how Aβ production normally occurs. It has been known for some time that Aβ secretion is activity-dependent, but the precise mechanisms are only now starting to be delineated. The prevailing model for APP processing was that it took place in axons/synaptic boutons and was in some way related to synaptic vesicle recycling. This study and a few other studies from the Holtzman, Malinow, and Worley groups (Verges et al., 2011; Wu et al., 2011; and Kamenetz et al., 2003) now highlight the role of APP processing and Aβ production in dendrites. Indeed, one of the putative physiological functions proposed for Aβ is to regulate postsynaptic AMPA type glutamate receptor levels (Kamenetz et al., 2003) in a negative feed-back cycle. Synaptic dysfunction in Alzeheimer’s disease thus may result from poor neuronal homeostasis.
Verges DK, Restivo JL, Goebel WD, Holtzman DM, Cirrito JR. Opposing synaptic regulation of amyloid-β metabolism by NMDA receptors in vivo. J Neurosci. 2011 Aug 3;31(31):11328-37. PubMed.
Wu J, Petralia RS, Kurushima H, Patel H, Jung MY, Volk L, Chowdhury S, Shepherd JD, Dehoff M, Li Y, Kuhl D, Huganir RL, Price DL, Scannevin R, Troncoso JC, Wong PC, Worley PF. Arc/Arg3.1 regulates an endosomal pathway essential for activity-dependent β-amyloid generation. Cell. 2011 Oct 28;147(3):615-28. PubMed.
Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R. APP processing and synaptic function. Neuron. 2003 Mar 27;37(6):925-37. PubMed.View all comments by Jason Shepherd
Rutgers - New Jersey Medical School
This paper by Das et al. extends previous studies that indicated that endosomes—specifically, the early and recycling endosomes—are major sites of cleavage of Aβ precursor protein (APP) by β-secretase. It also provides additional support for the notion that the amyloidogenic processing of APP is potentiated by neuronal activity. Using live imaging of fluorescently tagged APP and BACE-1 (the major β-secretase), the authors also provide data supporting the hypothesis that APP is processed by diverting it to recycling endosomes, where BACE-1 normally accumulates. We agree that this is one of several ways by which amyloidogenic processing of APP could occur, and wholeheartedly recommend this paper. Here, we would like to comment on the intraneuronal sites, other than the synapse, where AD-relevant APP processing could occur.
Das et al. focus on the processing of APP in dendrites, and the clear suggestion is that APP cleavage by β-secretase occurs within the dendrites, at postsynaptic sites. While there is no doubt that processing of APP in neuronal processes is robust, we would like to stress that the endosomes localized in neurites are not the exclusive sites of intraneuronal APP processing, and that compartments in the soma also contribute to the cleavage of APP by β-secretase. Newly synthesized APP is extensively transported to the plasma membrane, and is thereafter retrieved by endocytosis and delivered to early and recycling endosomes in the soma that contain large amounts of β-secretase. In our studies, we also find that the levels of BACE1 in the soma by far exceed those present in neurites (see Muresan and Mursean, 2006). In addition to endosomes, β-secretase is present throughout the early secretory pathway: in the endoplasmic reticulum (ER), the ER-Golgi intermediate compartment (ERGIC), the Golgi apparatus, and in the trans-Golgi network (TGN) (see Thinkaran and Koo, 2008, Vassar et al., 2009). Das et al. also find that APP and β-secretase colocalize at the level of ER and Golgi. Although the general view is that β-secretase activity in these less-acidic compartments would be low, it is hard to believe that it is completely suppressed. In fact, earlier studies have reported APP processing in the ER and ERGIC (see Cook et al., 1997).
Those of us who listened to Charles Glabe’s talk at the AD/PD Conference in Florence earlier this year should have been impressed with the strong data suggesting that significant proteolytic processing of APP in Alzheimer’s disease could in fact occur in the neuronal soma, rather than at the synaptic terminal. To us, the interpretation that Aβ-loaded cell bodies could also be responsible for the initiation of the neuritic plaques is likely correct. Our own immunohistochemical data on paraffin sections from AD brain and on cryosections from a mouse model of AD (Bruce Lamb’s R1.40 mouse) support this interpretation. This is not to say that significant APP cleavage, and generation of Aβ, does not also occur at the synapse. We only want to draw attention to the possibility that the processing of APP, and the generation of AD-relevant APP fragments (CTFβ, sAPPβ, in addition of Aβ), also occur—perhaps to a large extent—in the neuronal soma. Although the synapse is a major site of the neuronal pathology in AD, and the processing of APP (with generation and subsequent secretion of Aβ) is likely regulated by synaptic activity (see Cirrito et al., 2008, Tampellini and Gouras, 2010), the neuronal activity could also affect processing of APP in the soma, via retrograde signaling, for example. It would be naive to rule out this latter possibility.
Glabe, C., Conformational Diversity of Amyloid in Human AD Brain. The 11th International Conference on Alzheimer’s & Parkinson’s Disease, Florence, Italy, March 6-10, 2013. ARF related story
Muresan Z, Muresan V. Neuritic deposits of amyloid-beta peptide in a subpopulation of central nervous system-derived neuronal cells. Mol Cell Biol. 2006 Jul;26(13):4982-97. PubMed.
Thinakaran G, Koo EH. Amyloid precursor protein trafficking, processing, and function. J Biol Chem. 2008 Oct 31;283(44):29615-9. PubMed.
Vassar R, Kovacs DM, Yan R, Wong PC. The beta-secretase enzyme BACE in health and Alzheimer's disease: regulation, cell biology, function, and therapeutic potential. J Neurosci. 2009 Oct 14;29(41):12787-94. PubMed.
Cook DG, Forman MS, Sung JC, Leight S, Kolson DL, Iwatsubo T, Lee VM, Doms RW. Alzheimer's A beta(1-42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells. Nat Med. 1997 Sep;3(9):1021-3. PubMed.
Cirrito JR, Kang JE, Lee J, Stewart FR, Verges DK, Silverio LM, Bu G, Mennerick S, Holtzman DM. Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo. Neuron. 2008 Apr 10;58(1):42-51. PubMed.
Tampellini D, Gouras GK. Synapses, synaptic activity and intraneuronal abeta in Alzheimer's disease. Front Aging Neurosci. 2010;2 PubMed.View all comments by Virgil Muresan
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