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Goetzl EJ, Boxer A, Schwartz JB, Abner EL, Petersen RC, Miller BL, Kapogiannis D. Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease. Neurology. 2015 Jul 7;85(1):40-7. Epub 2015 Jun 10 PubMed.
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University of Goteborg, Sahlgrenska University Hospital
This is an interesting study with large potential, since it identifies a set of candidate AD biomarkers in blood exosomes. The principle of isolating exosomes and quantifying specific candidate protein biomarkers is an attractive approach to identifying novel AD biomarkers. Indeed, the identified biomarker candidates cathepsin D, LAMP-1, ubiquitinylated proteins, and HSP70 fit well with the recent interest in the relevance of a autophagocytic-lysosomal dysfunction in AD.
The results need to be validated in larger cohorts. However, a concern is how certain we can be that these "neural-derived plasma exosomes” are derived from the brain. To pull out (or affinity-purify) neural-derived exosomes from plasma, an antibody against CD171 (L1CAM neural adhesion protein) called clone 5G3 was used. However, CD171 is also expressed on blood cells (monocytes and lymphocytes), blood vessels, the peripheral nervous system, collecting tubules of the kidney and in many types of tumor (Huszar et al., 2006; Felding-Habermann et al., 1997). Even if this peripheral expression may not limit the use of plasma exosome proteins as AD biomarkers, it may act as a confounder when aiming at linking plasma exosome levels (or protein levels in plasma exosomes) to brain molecular pathology, and introduce noise due to, for example, peripheral inflammation or other conditions. Nevertheless, the findings are clearly interesting and warrant replication in independent studies.
References:
Huszar M, Moldenhauer G, Gschwend V, Ben-Arie A, Altevogt P, Fogel M. Expression profile analysis in multiple human tumors identifies L1 (CD171) as a molecular marker for differential diagnosis and targeted therapy. Hum Pathol. 2006 Aug;37(8):1000-8. Epub 2006 Jun 21 PubMed.
Felding-Habermann B, Silletti S, Mei F, Siu CH, Yip PM, Brooks PC, Cheresh DA, O'Toole TE, Ginsberg MH, Montgomery AM. A single immunoglobulin-like domain of the human neural cell adhesion molecule L1 supports adhesion by multiple vascular and platelet integrins. J Cell Biol. 1997 Dec 15;139(6):1567-81. PubMed.
View all comments by Kaj BlennowALSP, Inc.
Goetzl et al. show that Alzheimer’s disease and frontotemporal dementia patients have differences in biomarkers located within blood exosomes secreted by brain neuronal cells. These biomarker differences could potentially become diagnostic for these diseases, and thus this is an important paper. While the use of exosomes as a potential diagnostic pool is not new (e.g., Kang et al., 2014), this is among the first publications to use neuronally derived exosomes to diagnose dementias, and as such is of particular interest to the readers of this forum.
Exosomes come from the cytosol of cells and thus exosome analysis is of the cellular cytosolic composition. Current methods of probing brain composition in patients rely on cerebrospinal fluid, which only allows study of the composition of the extracellular space. As such, this paper opens new opportunities for evaluating the intracellular composition of neurons and glial cells in patients. This has many potential applications, such as estimating the dose of a therapeutic agent in neurons rather than only in the extracellular space, as is the case now.
Some key findings of the paper are that cathepsin D (CatD) and lysosome-associated membrane protein 1 (LAMP1) levels are significantly elevated and heat-shock protein 70 (HSP70) is reduced in neuronally derived exosomes from AD patients relative to controls. These data are important because they show that in AD patients, there is lysosomal breakdown and cathepsin D release to the cytoplasm. That is direct support for the “calpain-cathepsin” cell-death hypothesis of AD (Yamashima, 2013), which is that calpain activation reduces HSP70, causing lysosomal membrane permeabilization and the release of lysosomal CatD (as well as cathepsin B and L) to the cytoplasm, where its proteolytic activity results in cell death and inflammation of AD. A practical application of these findings is that there are now markers that can be used to evaluate in patients the potential of therapeutic compounds to affect this form of cell death.
References:
Kang GY, Bang JY, Choi AJ, Yoon J, Lee WC, Choi S, Yoon S, Kim HC, Baek JH, Park HS, Lim HJ, Chung H. Exosomal proteins in the aqueous humor as novel biomarkers in patients with neovascular age-related macular degeneration. J Proteome Res. 2014 Feb 7;13(2):581-95. Epub 2014 Jan 16 PubMed.
Yamashima T. Reconsider Alzheimer's disease by the 'calpain-cathepsin hypothesis'-A perspective review. Prog Neurobiol. 2013 Jun;105:1-23. PubMed.
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