Elsevier

Neurobiology of Aging

Volume 31, Issue 4, April 2010, Pages 715-718
Neurobiology of Aging

Brief communication
Matrix metalloproteinase 3 haplotypes and plasma amyloid beta levels: The Rotterdam Study

https://doi.org/10.1016/j.neurobiolaging.2008.05.033Get rights and content

Abstract

Experimental studies suggest that matrix metalloproteinases (MMPs) are involved in the degradation of amyloid beta (Aβ) protein which plays a key role in the pathogenesis of Alzheimer's disease. Whether MMPs are associated with changes in beta amyloid levels in humans remains unclear. We related common haplotypes within the gene encoding MMP-3 with plasma levels of Aβ1–40 and Aβ1–42 in 1621 non-demented participants of the population-based Rotterdam Study. In non-demented persons, plasma Aβ concentration reflect levels of Aβ in the brain. DNA was genotyped for polymorphisms 1187 (5A6A, rs3025058), 2092A>G (rs522616), 9775T>A (rs563096) and 6658T>C (rs3025066) and haplotypes reconstructed (coding from 1187 (5A6A), 2092A>G, 9775T>A and 6658T>C: haplotype 1 = 5A-A-T-T, haplotype 2 = 6A-G-T-T, haplotype 3 = 6A-A-T-T, haplotype 4 = 6A-A-A-T and haplotype 5 = 5A-A-T-C). Then the associations of these haplotypes with plasma Aβ1–40 and Aβ1–42 levels were assessed using the program Haplo.Stats. Compared with haplotype 1, haplotype 4 was associated with significantly lower levels of plasma Aβ1–40 (β = −8.04, 95% CI (−14.79; −1.28), p = 0.02) after adjusting for age and sex. Haplotype 2 was associated with significantly higher levels of plasma Aβ1–42 (β = 3.70, 95% CI (1.75; 5.65), p = 0.0002). Our observations suggest that variation in the gene encoding MMP-3 is associated with changes in amyloid beta levels in humans. Factors modulating secretion or activity of MMP-3 may have the potential to influence the amount of Aβ concentration and deposition in the brain.

Introduction

One of the key hallmarks of Alzheimer's disease (AD) is the formation of amyloid plaques in the brain. The main constituent of AD plaques is amyloid beta (Aβ) peptide, cleaved from the membrane-bound amyloid precursor protein (APP). Aggregation of Aβ into plaques is concentration-dependent, and mechanisms regulating extracellular Aβ levels are likely to play a major role in amyloid plaque formation. Although the exact mechanisms underlying the interaction between brain and plasma Aβ remain unclear, under normal physiological conditions a steady-state level of brain Aβ exists that is maintained by a balance between brain production and deposition of Aβ (Deane et al., 2003, DeMattos et al., 2002) and peripheral production by platelets (Chen et al., 1995, DeMattos et al., 2002). In healthy individuals, brain Aβ levels are therefore reflected by plasma Aβ concentration (DeMattos et al., 2002). In patients with dementia, due to deposition of Aβ in amyloid plaques, the correlation between Aβ levels in brain and plasma is less clear (Mehta et al., 2000).

Evidence by experimental studies suggests that several proteases may contribute to catabolism of Aβ. Promising candidate proteases for regulation of extracellular Aβ are matrix metalloproteinases (MMPs): they are being secreted and activated in the extracellular compartment, and are expressed in astrocytes, which in turn are found in the surroundings of amyloid plaques and mediate Aβ degradation in the extracellular space (Wyss-Coray et al., 2003). Moreover, MMP activity is induced in the presence of Aβ (Deb et al., 2003). Of major interest may be MMP-3 (Stromelysin-1): it activates several latent-type MMPs such as MMPs −1, −8, −9 and −13, which were involved in Aβ degradation in animal studies (Backstrom et al., 1996, Roher et al., 1994, White et al., 2006), and has also been reported to degrade Aβ itself (White et al., 2006).

To our knowledge, there is no observational study exploring the effect of MMP-3 on Aβ concentration in humans. Here we explored the impact of haplotypes representing the complete genetic variation in the gene encoding MMP-3 on plasma levels of Aβ1–40 and Aβ1–42 in 1621 non-demented participants of the population-based Rotterdam Study.

Section snippets

Participants and setting

The Rotterdam Study is a population-based prospective cohort study among 7983 participants that has been described elsewhere (Hofman et al., 1991, Hofman et al., 2007). From the baseline cohort we drew a random subcohort of 1756 non-demented persons in which we assessed plasma Aβ levels in blood samples taken at baseline. From this random sample, we excluded 128 persons (7.3%) due to missing MMP-3 genotyping and 7 (0.4%) due to Aβ outside detection limits. The final analytic sample included

Results

Genotypic distributions and demographic and clinical characteristics of the participants are shown in Table 1. Genotype distributions for all tagging SNPs were in HWE. Haplotypes were present in the following frequencies—haplotype 1 (5A-A-T-T): 43.6%, haplotype 2 (6A-G-T-T): 21.1%, haplotype 3 (6A-A-T-T): 14.4%, haplotype 4 (6A-A-A-T): 13.9%, haplotype 5 (5A-A-T-C): 6.8%. Since haplotype 1 was the most frequent haplotype, it served as reference category in further analyses. Compared with

Discussion

In this study, haplotype 4 was associated with significantly lower levels of plasma Aβ1–40 than haplotype 1. Haplotype 2 was associated with significantly higher levels of Aβ1–42. To our knowledge, this is the first study evaluating the association between MMPs and Aβ levels in a population-based setting. The chosen approach of exploring the impact of genetic variation in the MMP-3 gene on Aβ levels rather than using MMP-3 plasma or serum levels overcomes potential issues of residual

Conflict of interest

None.

Acknowledgements

Funding: Support was provided by Erasmus Medical Center, Erasmus University Rotterdam, the Netherlands Organization for Scientific Research (NWO), the Netherlands Organization for Health Research and Development (ZonMW), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European Commission (DG XII), the Municipality of Rotterdam, Pfizer Pharmaceutical Company, Ann Arbor. Support for this

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