Cited by 31Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchProtease and Inhibitor Mechanisms

A new role for matrix metalloproteinase-3 in the NGF metabolic pathway: Proteolysis of mature NGF and sex-specific differences in the continuum of Alzheimer's pathology

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Pentz, Rowan, Iulita, M. Florencia, Mikutra-Cencora, Maya, Ducatenzeiler, Adriana, Bennett, David A., Cuello, A. Claudio·2021·Neurobiology of Disease

Abstract

Matrix metalloproteinase-3 (MMP-3) has been associated with risk of Alzheimer's disease (AD). In this study we introduce a novel role for MMP-3 in degrading nerve growth factor (NGF) in vivo and examine its mRNA and protein expression across the continuum of AD pathology. We provide evidence that MMP-3 participates in the degradation of mature NGF in vitro and in vivo and that it is secreted from the rat cerebral cortex in an activity-dependent manner. We show that cortical MMP-3 is upregulated in the McGill-R-Thy1-APP transgenic rat model of AD-like amyloidosis. A similar upregulation was found in AD and MCI brains as well as in cognitively normal individuals with elevated amyloid deposition. We also observed that frontal cortex MMP-3 protein levels are higher in males. MMP-3 protein correlated with more AD neuropathology, markers of NGF metabolism, and lower cognitive scores in males but not in females. These results suggest that MMP-3 upregulation in AD might contribute to NGF dysmetabolism, and therefore to cholinergic atrophy and cognitive deficits, in a sex-specific manner. MMP-3 should be further investigated as a biomarker candidate or as a therapeutic target in AD.

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  • Among the most upregulated DEGs, higher amounts of MMP3, IBSP, or TAGLN in the brain have been linked to increased risk of AD.

    “Among the most upregulated DEGs, higher amounts of MMP3 (52), IBSP (53), or TAGLN (54) in the brain have been linked to increased risk of AD.”

    From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [52]

    The Results section, “Alterations of MMP-3 levels in the human cerebral cortex through the continuum of AD pathology” (page not supplied), reports higher brain MMP-3 in AD, MCI, and cognitively normal people with AD-like pathology. It also links higher MMP-3 to greater amyloid burden. These findings support an association with AD pathology, but the paper does not show that higher brain MMP-3 predicts an increased risk of developing AD. Citation (52) is attached to MMP3, not IBSP or TAGLN. (LLM, conf=0.84)

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1 of the 93 references couldn’t be matched to a known paper.

Research works printed but not linked: 6

  1. Cuello AC, 1993 Trophic responses of forebrain cholinergic neurons. Progress in brain research. 98, 265– 265. 8248516
  2. Iulita MF,, 2014b Intracellular Aβ pathology and early cognitive impairments in a transgenic rat overexpressing human amyloid precursor protein: a multidimensional study. Acta neuropathologica communications. 2, 61. 24903713 PMC4229908
  3. Iulita MF,, 2014c Nerve growth factor metabolic dysfunction in Down’s syndrome brains. Brain. 137, 860– 872. 24519975 PMC3927704
  4. Paxinos G, Watson C, 2006 The rat brain in stereotaxic coordinates: hard cover edition. Elsevier. 6110810
  5. Stomrud E,, 2010b Alterations of matrix metalloproteinases in the healthy elderly with increased risk of prodromal Alzheimer’s disease. 2, 20. PMC2919700 20576109
  6. Yamanaka H,, 2000 Serum matrix metalloproteinase 3 as a predictor of the degree of joint destruction during the six months after measurement, in patients with early rheumatoid arthritis. Arthritis. 43, 852– 858. 10765930

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Authors
Pentz, R., Iulita, M. F., Mikutra-Cencora, M., Ducatenzeiler, A., Bennett, D. A., & Cuello, A. C.
Affiliations
  • McGill University (CA)
  • Universitat Autònoma de Barcelona (ES)
  • Rush University Medical Center (US)
Corresponding author
Cuello, A. Claudio
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2021-01
Volume
148
Pages
105150
ISSN
0969-9961 (ISSN-L)
OpenAlex
W3097891564
Cited by
31
References
93
Citations by year
2026: 4 · 2025: 4 · 2024: 5 · 2023: 6 · 2022: 6 · 2021: 5 · 2020: 1
FWCI
2.71
Type
journal article
Language
en
Open access
Locations
  • Neurobiology of Disease (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institutes of Health
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
Keywords
matrix metalloproteinase-3, nerve growth factor, Alzheimer's disease, sex differences, amyloidosis, cognitive impairment, frontal cortex, biomarkers, therapeutic target, mild cognitive impairment
MeSH terms
Alzheimer Disease, Animals, Brain, Cerebral Cortex, Female, Male, RNA, Messenger, Sex Factors, Matrix Metalloproteinase 3, Nerve Growth Factor, Rats, Rats, Transgenic, Proteolysis, Cognitive Dysfunction

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