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Cited by 17Alzheimer's disease research and treatmentsProtease and Inhibitor MechanismsDementia and Cognitive Impairment Research

Investigation of the role of matrix metalloproteinases in the genetic etiology of Alzheimer's disease

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Hoogmartens, Julie, Hens, Elisabeth, Engelborghs, Sebastiaan, De Deyn, Peter Paul, van der Zee, Julie, Van Broeckhoven, Christine, Cacace, Rita·2021·Neurobiology of Aging
DOI 10.1016/j.neurobiolaging.2021.03.011
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Abstract

Matrix metalloproteinases (MMPs) are a multigene family of proteinases regulating the functions of a large number of signaling and scaffolding molecules that are involved in neuro-inflammation, synaptic dysfunction and neuronal death. MMPs have been associated with neurological conditions, such as Alzheimer's disease (AD), through a sudden and massive upregulation of particular members of the MMP family. Evidence for this hypothesis can be found in the clinical observation of increased MMP1 and MMP3 expression levels in plasma of AD patients compared to control individuals and in the pro-amyloidogenic effects that have been described for additional MMP family members like MMP13, MT1-MMP, and MT5-MMP. Consequently, we investigated the role of MMP1, 3, 13, MT1-MMP, and MT5-MMP in the genetic etiology of AD. We performed full exonic resequencing of these 5 MMPs in 1278 AD patients (mean age at onset [AAO]: 74.88 ± 9.10, range: 29-96) and 797 age-matched control individuals (mean age at inclusion [AAI]: 74.92 ± 6.48, range: 65-100) from Flanders-Belgium and identified MMP13 as most promising candidate gene. We identified 6 ultra-rare (≤0.01%) MMP13 missense mutations in 6 patients that were absent from the control cohort. We observed in one control individual a frameshift mutation (p.G269Qfs*2) leading to a premature termination codon. Based on previously described functional evidence, suggesting that MMP13 regulates BACE1 processing, and our genetic findings, we hypothesize a gain-of-function disease mechanism for the missense mutations found in patients. Functional experimental studies remain essential to assess the effect of these mutations on disease related processes and genetic replication studies are needed to corroborate our findings.

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  • Upregulation of MMP genes has been linked to neuroinflammation in AD.

    “upregulation of MMP genes has been linked neuroinflammation in AD (73, 85)”

    From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [73]

    The Introduction links MMPs to regulation of inflammatory processes in AD, and the Discussion describes upregulation of some MMP family members in neurological conditions. Neither passage specifically links MMP gene upregulation to neuroinflammation in AD; the paper’s own brain-tissue analysis found no detectable MMP13 protein expression in either AD patients or controls (section 3.3). Page numbers are unavailable in our copy. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • MMPs are known to be linked to extracellular protein degradation including Aβ, whereas MMPs upregulated in AD may also confer neuroinflammation, synaptic dysfunction, and neuronal death.

    “MMPs are known to be linked to extracellular protein degradation including Aβ (72), whereas MMPs upregulated in AD may also confer neuroinflammation, synaptic dysfunction, and neuronal death (73, 74).”

    From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [73]

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Authors
Hoogmartens, J., Hens, E., Engelborghs, S., De Deyn, P. P., van der Zee, J., Van Broeckhoven, C., & Cacace, R.
Affiliations
  • University of Antwerp (BE)
  • Vrije Universiteit Brussel (BE)
Corresponding author
Cacace, Rita
ORCID
Venue
Neurobiology of Aging
Publisher
Elsevier BV
Published
2021-08
Volume
104
Pages
105.e1-105.e6
ISSN
0197-4580 (ISSN-L)
DOI
10.1016/j.neurobiolaging.2021.03.011
OpenAlex
W3145043910
Cited by
17
References
1
Citations by year
2026: 3 · 2025: 3 · 2024: 4 · 2023: 3 · 2022: 3 · 2021: 1
FWCI
1.74
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurobiology of Aging (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • VUBIR (Vrije Universiteit Brussel) (submittedVersion)
Funders
  • Fonds Wetenschappelijk Onderzoek
  • Vlaamse regering
  • Instituut Born-Bunge
  • Universitair Ziekenhuis Antwerpen
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
matrix metalloproteinases, Alzheimer's disease, genetic etiology, MMP-13, missense mutations, frameshift mutation, gain-of-function mechanism, MT1-MMP, MMP-1, MMP-3, amyloid-beta, neuroinflammation, exome resequencing
MeSH terms
Adult, Aged, Aged, 80 and over, Alzheimer Disease, Female, Humans, Male, Middle Aged, Aspartic Acid Endopeptidases, Mutation, Missense, Matrix Metalloproteinase 13, Amyloid Precursor Protein Secretases, Genetic Association Studies

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