Analysis of Matrix Metallo-Proteases and the Plasminogen System in Mild Cognitive Impairment and Alzheimer's Disease Cerebrospinal Fluid

Article type: Research Article

Authors: Hanzel, Cecilia E.^{a; 1} | Iulita, M. Florencia^{a; 1} | Eyjolfsdottir, Helga^{d; e} | Hjorth, Erik^d | Schultzberg, Marianne^d | Eriksdotter, Maria^{d; e} | Cuello, A. Claudio^{a; b; c; *}

Affiliations: [a] Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada | [b] Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada | [c] Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada | [d] Department of Neurobiology, Care Sciences & Society, Karolinska Institutet, Stockholm, Sweden | [e] Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden

Correspondence: [*] Correspondence to: Dr. A. Claudio Cuello, Department of Pharmacology and Therapeutics, McGill University, 3655 Sir-William-Osler Promenade, Room 1210, Montreal, Quebec, H3G 1Y6, Canada. Tel.: +1 514 398 3618; Fax: +1 514 398 8317; E-mail: claudio.cuello@mcgill.ca.

Note: [1] These authors contributed equally to this work.

Abstract: The expression of matrix metallo-proteases (MMP-2, MMP-3, MMP-7, and MMP-9), plasminogen and their regulators (TIMP-1, tissue plasminogen activator and neuroserpin) was investigated in cerebrospinal fluid (CSF) from subjective cognitive impairment (SCI) subjects, mild cognitive impairment (MCI), and Alzheimer's disease (AD) cases. ELISA analysis revealed a significant increase in MMP-3 protein levels in CSF from AD subjects, compared to age-matched SCI and MCI cases. No significant differences in MMP-2 and MMP-9 protein levels were detected between the three groups. MMP-7 was undetectable in all three groups. MCI individuals exhibited increased levels of the metallo-protease inhibitor TIMP-1 in CSF as well as higher plasminogen and neuroserpin expression, compared to SCI subjects. Levels of tissue plasminogen activator (tPA) were significantly reduced in AD CSF. Correlation analysis revealed a significant positive association between MMP-3, p-tau, and total-tau levels. Conversely, there was a significant negative correlation between this protease and Mini-Mental State Examination (MMSE) scores. tPA positively correlated with amyloid-β levels in CSF and with MMSE scores. Our results suggest that MMP-3 and tPA, in combination with current amyloid-β and tau biomarkers, may have potential as surrogate indicators of an ongoing AD pathology.

Keywords: Alzheimer's disease, biomarkers, metallo-proteases, neuroserpin, plasminogen

DOI: 10.3233/JAD-132282

Journal: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 667-678, 2014