{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:31Z","timestamp":1787028571812,"version":"build-2736575974"},"reference-count":42,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T00:00:00Z","timestamp":1757635200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Defense (DOD) Amyotrophic Lateral Sclerosis Research Program (ALSRP) Therapeutic Development Award (TDA)","award":["W81XWH-21-ALSRP-DTA"],"award-info":[{"award-number":["W81XWH-21-ALSRP-DTA"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Matrix metalloproteinases 2 and 9 (MMP-2, MMP-9) have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, their protein levels and correlation with other biomarkers are not well understood. We measured total and active MMP-2\/-9 and additional biomarkers (creatinine, neurofilament light, cystatin C, and alkaline phosphatase) in the serum of people with ALS (ALS, n = 30) and compared their levels with age-matched healthy controls (HC, n = 20) and other neurological diseases (diabetic nephropathy, Alzheimer\u2019s disease, Parkinson\u2019s disease; n = 8 each). We also measured MMP-2\/-9 in a set of CSF samples from ALS (n = 30) and age-matched other neurological diseases (OND, n = 14). Lastly, we measured the competitive binding behavior of a dual MMP-2\/MMP-9 inhibitor, AQU-118, against active MMP-9 in situ within the serum of ALS. We found significantly elevated levels of both total MMP-9 protein (two studies, 7.5 and 9.5-fold; both p &lt; 0.0001) and active MMP-9 (2.5-fold; p &lt; 0.0001) in ALS serum compared to HC. Serum NfL was significantly elevated (6-fold, p &lt; 0.0001) and serum creatinine was significantly decreased (40%, p &lt; 0.0001) in ALS compared to HC. There were significantly decreased levels of MMP-2 (two studies, 26 and 33%; p &lt; 0.001 and p = 0.0001, respectively) in the serum of ALS as compared to HC. ALS also had significantly higher active MMP-9 in serum than patients with Alzheimer\u2019s disease and higher than Parkinson\u2019s disease or diabetic nephropathy. We confirmed that active MMP-9 in ALS is fully available for proteolytic activity in both serum and CSF and can be inhibited using an MMP-2\/-9 inhibitor. Active MMP-9 is systemically elevated in ALS and therefore a therapeutic target for ALS drug development.<\/jats:p>","DOI":"10.3390\/ijms26188900","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T12:34:03Z","timestamp":1757680443000},"page":"8900","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["ALS Patients Exhibit Altered Levels of Total and Active MMP-9 and Several Other Biomarkers in Serum and CSF Compared to Healthy Controls and Other Neurologic Diseases"],"prefix":"10.3390","volume":"26","author":[{"given":"Robert","family":"Bowser","sequence":"first","affiliation":[{"name":"nVector, Inc, 124 W. Thomas Road STE 200, Phoenix, AZ 85013, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiyan","family":"An","sequence":"additional","affiliation":[{"name":"nVector, Inc, 124 W. Thomas Road STE 200, Phoenix, AZ 85013, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Advansta, Inc., 2140 Bering Drive, San Jose, CA 95131, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert L.","family":"Sucholeiki","sequence":"additional","affiliation":[{"name":"Boston University School of Medicine, 72 E. Concord St., Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9937-5050","authenticated-orcid":false,"given":"Irving","family":"Sucholeiki","sequence":"additional","affiliation":[{"name":"Aquilus Pharmaceuticals, Inc., 225 Mystic Valley Parkway, Winchester, MA 01890, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,12]]},"reference":[{"key":"ref_1","first-page":"113","article-title":"Matrix metalloproteinases (with accent to collagenases)","volume":"5","author":"Bilana","year":"2011","journal-title":"J. Cell Anim. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.bbamcr.2009.09.015","article-title":"Matrix metalloproteinases: What do they not do? New substrates and biological roles identified by murine models and proteomics","volume":"1803","author":"Rodriguez","year":"2010","journal-title":"Biochem. Biophys. 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