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. 2010 Jun 24;2(3):20.
doi: 10.1186/alzrt44.

Alterations of matrix metalloproteinases in the healthy elderly with increased risk of prodromal Alzheimer's disease

Erik Stomrud  1 , Maria Björkqvist, Sabina Janciauskiene, Lennart Minthon, Oskar Hansson
Affiliations

Alterations of matrix metalloproteinases in the healthy elderly with increased risk of prodromal Alzheimer's disease

Erik Stomrud et al. Alzheimers Res Ther. .

Abstract

Introduction: Matrix metalloproteinases (MMP) are believed to be involved in the pathologic processes behind Alzheimer's disease (AD). In this study, we aimed to examine the cerebrospinal fluid (CSF) levels of MMPs and tissue inhibitors of metalloproteinase-1 (TIMP-1) in individuals with AD dementia and cognitively healthy elderly individuals, and to investigate their relationship with established CSF biomarkers for Alzheimer's disease.

Methods: CSF was collected from 38 individuals with AD dementia and 34 cognitively healthy elderly individuals. The CSF was analyzed for MMP-1, MMP-3, MMP-9, TIMP-1, beta-amyloid1-42 (Abeta42), total tau protein (T-tau) and phosphorylated tau protein (P-tau). MMP/TIMP-1 ratios were calculated. APOE genotype was determined for the participants.

Results: AD patients had higher MMP-9/TIMP-1 ratios and lower TIMP-1 levels compared to cognitively healthy individuals. In AD patients, the MMP-9/TIMP-1 ratio correlated with CSF T-tau, a marker of neurodegeneration. Interestingly, the cognitively healthy individuals with risk markers for future AD, i.e. AD-supportive CSF biomarker levels of T-tau, P-tau and Abeta42 or the presence of the APOE epsilon4 allele, had higher CSF MMP-3 and MMP-9 levels and higher CSF MMP-3/TIMP-1 ratios compared to the healthy individuals without risk markers. The CSF levels of MMP-3 and -9 in the control group also correlated with the CSF T-tau and P-tau levels.

Conclusions: This study indicates that MMP-3 and MMP-9 might be involved in early pathogenesis of AD and that MMPs could be associated with neuronal degeneration and formation of neurofibrillary tangles even prior to development of overt cognitive dysfunction.

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Figures

Figure 1
Figure 1
Scatter plot of CSF MMP-9/TIMP-1 ratio and CSF T-tau levels in patients with Alzheimer's disease. CSF T-tau levels are presented in ng/l. CSF, cerebrospinal fluid; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinase.
Figure 2
Figure 2
Scatter plot of CSF MMP-3/TIMP-1 ratio and CSF T-tau levels in patients with Alzheimer's disease. CSF T-tau levels are presented in ng/l. CSF, cerebrospinal fluid; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinase.
Figure 3
Figure 3
Scatter plot of CSF MMP-9 levels and CSF T-tau levels in the cognitively healthy elderly individuals. CSF MMP-9 levels are presented in ng/ml and CSF T-tau levels are presented in ng/l. CSF, cerebrospinal fluid; MMP, matrix metalloproteinase.
Figure 4
Figure 4
Scatter plot of CSF MMP-9 levels and CSF P-tau levels in the cognitively healthy elderly individuals. CSF MMP-9 levels are presented in ng/ml and CSF P-tau levels are presented in ng/l. CSF, cerebrospinal fluid; MMP, matrix metalloproteinase.
Figure 5
Figure 5
Error plot of difference in CSF MMP-9 levels between the cognitively healthy elderly individuals with AD-indicative CSF biomarker levels (n = 7) compared with those with unaffected CSF biomarker levels (n = 27). CSF MMP-9 levels are presented in ng/ml. AD, Alzheimer's disease; CSF, cerebrospinal fluid; MMP, matrix metalloproteinase.
Figure 6
Figure 6
Error plot of difference in MMP-9 levels between cognitively healthy elderly individuals with at least one APOE ε4 allele (n = 9) compared with those without the allele (n = 25). CSF MMP-9 levels are presented in ng/ml. CSF, cerebrospinal fluid; MMP, matrix metalloproteinase.
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