Relationship between Cerebrospinal Fluid Matrix Metalloproteinases Levels and Brain Amyloid Deposition in Mild Cognitive Impairment

Sasaki, Yukie; Kimura, Noriyuki; Aso, Yasuhiro; Yabuuchi, Kenichi; Aikawa, Miki; Matsubara, Etsuro

doi:10.3390/biom11101496

Cited by 5 publications

(4 citation statements)

References 55 publications

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“…In related work, amyloid deposition is reduced in mice engineered to express high levels of MMP-9 ( Fragkouli et al, 2014 ; Yang et al, 2015 ). Similarly in human CSF, MMP-2 which shares substrate similarity with MMP-9, is negatively correlated with amyloid deposition as assessed by Pittsburgh compound B labeling ( Sasaki et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

CCR5 deficiency normalizes TIMP levels, working memory, and gamma oscillation power in APOE4 targeted replacement mice

Greco¹,

Rock²,

Amontree³

et al. 2023

Neurobiology of Disease

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Section: Discussionmentioning

confidence: 99%

CCR5 deficiency normalizes TIMP levels, working memory, and gamma oscillation power in APOE4 targeted replacement mice

Greco¹,

Rock²,

Amontree³

et al. 2023

Neurobiology of Disease

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“…Moreover, in amyloid depositing mice engineered to express high levels of MMP-9, amyloid deposition is also reduced (Fragkouli et al ., 2014; Yang et al ., 2015). Similarly in human CSF, MMP-2 which shares substrate similarity with MMP-9, is negatively correlated with amyloid deposition as assessed by Pittsburgh compound B labeling (Sasaki et al ., 2021). In a related study MMP-9 levels are reduced in AD patients as compared to controls (Mroczko et al ., 2014).…”

Section: Discussionmentioning

confidence: 99%

CCR5 deficiency normalizes TIMP levels, working memory, and gamma oscillation power in APOE4 targeted replacement mice

Greco

Rock

Amontree

et al. 2022

Preprint

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The APOE4 allele increases the risk for Alzheimers disease (AD) in a dose-dependent manner and is also associated with cognitive decline in non-demented elderly controls. In mice with targeted gene replacement (TR) of murine APOE with human APOE3 or APOE4, the latter show reduced neuronal dendritic complexity and impaired learning. APOE4 TR mice also show reduced gamma oscillation power and sharp wave ripple (SWR) abundance, neuronal population activities important to learning and memory. Published work has shown that brain extracellular matrix (ECM) can reduce neuroplasticity as well as gamma power and SWR abundance, while attenuation of ECM can instead enhance these endpoints. In the present study we examine human cerebrospinal fluid (CSF) samples from APOE3 and APOE4 individuals and brain lysates from APOE3 and APOE4 TR mice for levels of ECM effectors that can increase matrix deposition and restrict neuroplasticity. We find that CCL5, a molecule linked to ECM deposition in liver and kidney, is increased in CSF samples from APOE4 individuals. Levels of tissue inhibitor of metalloproteinases (TIMPs), which inhibit the activity of ECM-degrading enzymes, are also increased in APOE4 CSF as well as protein lysates from APOE4 TR mice. Importantly, as compared to wildtype/APOE4 heterozygotes, CCR5 knockout/APOE4 heterozygotes show reduced TIMP levels and enhanced EEG gamma power. The latter also show improved learning and memory, suggesting that the CCR5/CCL5 axis could represent a therapeutic target for APOE4 individuals.

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“…However, the co-occurrence of AD in these patients can significantly confound results when extrapolating these results to CAA pathology. Additionally, CSF MMP-2 has been shown to be associated with parenchymal amyloid deposition [ 37 ]. MMP activity studies using gelatin zymography have shown MMP-9 activity to be elevated in CSF of patients with vascular dementia, but not in patients with AD, when compared to controls [ 38 ].…”

Section: Introductionmentioning

confidence: 99%

Decreased ratios of matrix metalloproteinases to tissue-type inhibitors in cerebrospinal fluid in sporadic and hereditary cerebral amyloid angiopathy

et al. 2023

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Background To evaluate the potential of cerebrospinal fluid (CSF) levels of matrix metalloproteinases and tissue-type inhibitors (MMP; TIMP), and ratios of MMPs to TIMPs, to function as biomarkers for sporadic or hereditary cerebral amyloid angiopathy (CAA). Methods CSF concentrations of the matrix metalloproteinases MMP-2, MMP-9 and MMP-14, as well as the tissue inhibitors of metalloproteinases TIMP-1, TIMP-2 and TIMP-3, were determined using immunoassays. These assays were applied to two, independent study groups of sporadic CAA (sCAA) (n = 28/43) and control subjects (n = 40/40), as well as to groups of pre-symptomatic (n = 11) and symptomatic hereditary Dutch-CAA (D-CAA) patients (n = 12), and age-matched controls (n = 22/28, respectively). Results In the sCAA/control cohorts, inconsistent differences were found for individual MMPs and TIMPs, but MMP-2/TIMP-2 (discovery/validation: p = 0.004; p = 0.02) and MMP-14/TIMP-2 ratios (discovery/validation: p < 0.001; p = 0.04) were consistently decreased in sCAA, compared to controls. Moreover, MMP-14 was decreased in symptomatic D-CAA (p = 0.03), compared to controls. The MMP-14/TIMP-1 (p = 0.03) and MMP-14/TIMP-2 (p = 0.04) ratios were decreased in symptomatic D-CAA compared to controls and also compared to pre-symptomatic D-CAA (p = 0.004; p = 0.005, respectively). Conclusion CSF MMP-2/TIMP-2 and MMP-14/TIMP-2 were consistently decreased in sCAA, compared to controls. Additionally, MMP-14/TIMP-2 levels were also decreased in symptomatic D-CAA, compared to both pre-symptomatic D-CAA and controls, and can therefore be considered a biomarker for sporadic and late-stage hereditary forms of CAA.

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Relationship between Cerebrospinal Fluid Matrix Metalloproteinases Levels and Brain Amyloid Deposition in Mild Cognitive Impairment

Cited by 5 publications

References 55 publications

CCR5 deficiency normalizes TIMP levels, working memory, and gamma oscillation power in APOE4 targeted replacement mice

CCR5 deficiency normalizes TIMP levels, working memory, and gamma oscillation power in APOE4 targeted replacement mice

CCR5 deficiency normalizes TIMP levels, working memory, and gamma oscillation power in APOE4 targeted replacement mice

Decreased ratios of matrix metalloproteinases to tissue-type inhibitors in cerebrospinal fluid in sporadic and hereditary cerebral amyloid angiopathy

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