Choi Y, Park JH, Jo A, Lim CW, Park JM, Hwang JW, Lee KS, Kim YS, Lee H, Moon J. Blood-derived APLP1+ extracellular vesicles are potential biomarkers for the early diagnosis of brain diseases. Sci Adv. 2025 Jan 3;11(1):eado6894. Epub 2025 Jan 1 PubMed.
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Mayo Clinic Florida
This paper presents a compelling study that characterizes APLP1 as a brain-specific biomarker for extracellular vesicles (EVs) detectable in plasma. The study utilizes a publicly available proteomic database to assess APLP1 expression, with validation through immunohistochemistry and immunoblotting of mouse brain and peripheral tissues. The authors further explore the molecular composition of APLP1+ EVs enriched from plasma using proteomic and miRNA profiling, demonstrating an enrichment of neuronal molecules in these EVs as well as miRNAs targeting genes related to axon, cell, and nervous system development.
Additionally, they report an increased level of CD63+APLP1+ EVs in the plasma of glioblastoma multiforme (GBM) patients compared to healthy controls. The datasets provide valuable insight and suggest that APLP1 could serve as a novel marker for brain-derived EVs detectable in plasma.
It's noteworthy that APLP1 is primarily expressed in oligodendroglia, along with other glial cells and neurons. This makes it a promising candidate for use in disorders associated with oligodendroglia, including GBM, as highlighted here.
Our lab, along with others, has recently focused on identifying additional neuron-specific biomarkers such as ATP1A3 (You et al., 2023), GAP43 with NLGN3 (Eitan et al., 2023), and NRXN3 (Ter-Ovanesyan et al., 2024). These biomarkers have proven successful as plasma-based EV markers for Alzheimer's disease (AD), demonstrating their potential in neurodegenerative disease detection. These advancements align with the current study's approach, which also emphasizes plasma EVs as valuable diagnostic tools.
An interesting aspect of the paper is their use of fluorescence-labeled CD63+APLP1+ EVs to track and visualize these markers with single EV resolution, a technique that adds precision to diagnostic experiments. Given the low abundance of brain-derived EVs in plasma, techniques like high-resolution or super-resolution microscopy—such as direct stochastic optical reconstruction microscopy (dSTORM) (You et al., 2023)—will be crucial for enhancing the sensitivity and accuracy of plasma EV biomarkers in future diagnostic applications. Such methods will allow for more detailed observation of individual EVs, helping bridge the gap between plasma-based detection and clinical relevance.
References:
You Y, Zhang Z, Sultana N, Ericsson M, Martens YA, Sun M, Kanekiyo T, Ikezu S, Shaffer SA, Ikezu T. ATP1A3 as a target for isolating neuron-specific extracellular vesicles from human brain and biofluids. Sci Adv. 2023 Sep 15;9(37):eadi3647. PubMed.
Eitan E, Thornton-Wells T, Elgart K, Erden E, Gershun E, Levine A, Volpert O, Azadeh M, Smith DG, Kapogiannis D. Synaptic proteins in neuron-derived extracellular vesicles as biomarkers for Alzheimer's disease: novel methodology and clinical proof of concept. Extracell Vesicles Circ Nucl Acids. 2023 Mar;4(1):133-150. Epub 2023 Mar 31 PubMed.
Ter-Ovanesyan D, Whiteman S, Gilboa T, Kowal EJ, Trieu W, Iyer S, Budnik B, Babila CM, Heimberg G, Burgess MW, Keshishian H, Carr SA, Regev A, Church GM, Walt DR. Identification of markers for the isolation of neuron-specific extracellular vesicles. 2024 Apr 03 10.1101/2024.04.03.587267 (version 1) bioRxiv.
UCSF
Choi and colleagues employed a logical and systematic approach to screen for brain-derived extracellular vesicle (BDEV) markers, and to subsequently validate APLP1-positive EVs as “brain representatives” in plasma, using an impressive variety of methods. While the data suggest that APLP1 is specific for brain EVs, the fluorescent images intended to demonstrate co-localization of other markers with APLP1 at the individual EV level raise technical concerns. Specifically, the fluorescent puncta may represent aggregates rather than individual EVs, as details of the microscopy method are unfortunately not provided.
Whether the identification of APLP1 or another common BDEV marker could serve as a critical catalyst for developing clinical-level EV-based diagnostics for neurodegenerative and other brain disorders remains to be seen. An accurate diagnostic for neurodegenerative disorders within the same group, such as specific forms of tauopathy or synucleinopathy, will likely require the addition of cell-type-specific EV markers (e.g., Dutta et al., 2021). Novel neuron-specific EV markers, such as ATP1A3 (You et al., 2023), may help overcome the ambiguity associated with L1CAM.
Nevertheless, as a BDEV marker, APLP1 represents a valuable new tool and, as the authors aptly noted, is likely to be part of a future “symphony of multiple biomarkers for precise disease identification.”
References:
Dutta S, Hornung S, Kruayatidee A, Maina KN, Del Rosario I, Paul KC, Wong DY, Duarte Folle A, Markovic D, Palma JA, Serrano GE, Adler CH, Perlman SL, Poon WW, Kang UJ, Alcalay RN, Sklerov M, Gylys KH, Kaufmann H, Fogel BL, Bronstein JM, Ritz B, Bitan G. α-Synuclein in blood exosomes immunoprecipitated using neuronal and oligodendroglial markers distinguishes Parkinson's disease from multiple system atrophy. Acta Neuropathol. 2021 Sep;142(3):495-511. Epub 2021 May 15 PubMed. Correction.
You Y, Zhang Z, Sultana N, Ericsson M, Martens YA, Sun M, Kanekiyo T, Ikezu S, Shaffer SA, Ikezu T. ATP1A3 as a target for isolating neuron-specific extracellular vesicles from human brain and biofluids. Sci Adv. 2023 Sep 15;9(37):eadi3647. PubMed.
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