Neuroprotective role of MMP-9 overexpression in the brain of Alzheimer's 5xFAD mice

Fragkouli, Apostolia; Tsilibary, Effie C.; Τzinia, Athina K.

doi:10.1016/j.nbd.2014.06.021

Cited by 64 publications

(62 citation statements)

References 76 publications

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“…Previous reports have demonstrated that in primary neurons IRS1 phosphorylation was linked to the PI3K/Akt pathway through the action of BDNF 39, 40 . Moreover, in previous studies by us and others it was demonstrated that MMP-9 mediated the conversion of pro-BDNF to mature BDNF 20, 29, 41 and that reduced BDNF expression was observed in 5XFAD mice at the age of 7 months 42 . In the experiments described herein, we observed decreased levels of BDNF in 3 month-old 5XFAD mice compared to the wild type.…”

Section: Discussionmentioning

confidence: 78%

“…Similarly to these mechanisms, a key role of JNK activation in neuronal insulin resistance in the presence of Aβ oligomers was recently demonstrated 35 . We previously reported that overexpression of MMP-9 significantly reduced Aβ oligomers in the brain of 7 month-old 5XFAD mice 29 . Thereby, we investigated the effect of MMP-9 overexpression on the phosphorylation of JNK in our examination system.…”

Section: Resultsmentioning

confidence: 89%

“…In AD, MMP-9 has been extensively studied due to its potential role in amyloid clearance, since it was shown to degrade Aβ peptides in vitro and in vivo 23–25 . In this aspect we have previously reported that MMP-9 has a neuroprotective role in vitro and in vivo , by decreasing the formation of Aβ oligomers and by increasing the levels of neurotrophic factors, such as BDNF 26–29 .…”

Section: Introductionmentioning

confidence: 96%

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Overexpression of matrix metalloproteinase-9 (MMP-9) rescues insulin-mediated impairment in the 5XFAD model of Alzheimer’s disease

Kaminari

Giannakas

Τzinia

et al. 2017

Sci Rep

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A hallmark of Alzheimer’s disease (AD) is the accumulation of oligomeric amyloid-β (Aβ) peptide, which may be primarily responsible for neuronal dysfunction. Insulin signaling provides a defense mechanism against oligomer-induced neuronal loss. We previously described the neuroprotective role of matrix metalloproteinase 9 (MMP-9) in decreasing the formation of Aβ oligomers. In the present study, we examined the role of MMP-9 on the insulin survival pathway in primary hippocampal cultures and hippocampal cell extracts from 3 month-old wild type, AD (5XFAD), MMP-9-overexpressing (TgMMP-9), and double transgenic mice (5XFAD/TgMMP-9). The data demonstrate that the insulin pathway was compromised in samples from 5XFAD mice, when compared to the wild type and TgMMP-9. This was due to enhanced phosphorylation of IRS1 at Serine 636 (pIRS1-Ser636), which renders IRS1 inactive and prevents insulin-mediated signaling. In 5XFAD/TgMMP-9 samples, the insulin survival pathway was rescued through enhanced activation by phosphorylation of IRS1 at Tyrosine 465 (pIRS1-Tyr465), downstream increased phosphorylation of Akt and GSK-3β, and decreased phosphorylation of JNK kinase. Oligomeric Aβ levels decreased and BDNF levels increased in 5XFAD/TgMMP-9 mice, compared to 5XFAD mice. Our findings indicate that overexpression of MMP-9 rescued insulin survival signaling in vitro and in early stages in the 5XFAD model of AD.

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Section: Discussionmentioning

confidence: 78%

Section: Resultsmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 96%

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Overexpression of matrix metalloproteinase-9 (MMP-9) rescues insulin-mediated impairment in the 5XFAD model of Alzheimer’s disease

Kaminari

Giannakas

Τzinia

et al. 2017

Sci Rep

Self Cite

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“…TIMP-1, stem cell factor (SCF) and hepatocyte growth factor (HGF) also exhibit neuroprotective activities [54][55][56]. MMP-9 reduces the level of pathogenic Aβ oligomers in AD mice and restores synaptic and cognitive deficits in these mice [57], while transforming growth factor-β (TGF-β) modulates microglial activation [58]. The concentrations of these factors in SHED-CM may be quite low; however, we believe that the combinatorial effects of these factors in SHED-CM could provide therapeutic benefits for AD.…”

Section: Discussionmentioning

confidence: 99%

Conditioned medium from the stem cells of human dental pulp improves cognitive function in a mouse model of Alzheimer’s disease

Mita

Furukawa‐Hibi

Takeuchi

et al. 2015

Behavioural Brain Research

133

118

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“…Both groups identified the matrix metalloproteinase MT5-MMP as contributing to the -secretase cleavage of APP. Both soluble and membrane-bound matrix metalloproteinases have been of interest to the AD field for some time due to their capacity to proteolytically cleave APP and A␤ in vitro and in vivo (24,25). In the most recent work, -secretase was shown to cleave APP between Asn 504 -Met 505 , resulting in the shedding of an ϳ80 -95 kDa soluble fragment, leaving the novel membrane-bound CTF, CTF (Fig.…”

Section: -Secretasementioning

confidence: 99%

A Greek Tragedy: The Growing Complexity of Alzheimer Amyloid Precursor Protein Proteolysis

Andrew

Kellett

Wang

et al. 2016

Journal of Biological Chemistry

144

122

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Proteolysis of the amyloid precursor protein (APP) liberates various fragments including the proposed initiator of Alzheimer disease-associated dysfunctions, amyloid-␤. However, recent evidence suggests that the accepted view of APP proteolysis by the canonical ␣-, ␤-, and ␥-secretases is simplistic, with the discovery of a number of novel APP secretases (including ␦-and -secretases, alternative ␤-secretases) and additional metabolites, some of which may also cause synaptic dysfunction. Furthermore, various proteins have been identified that interact with APP and modulate its cleavage by the secretases. Here, we give an overview of the increasingly complex picture of APP proteolysis.Currently over 46 million people worldwide are living with dementia (see the Alzheimer's Disease International website) with Alzheimer disease (AD) 3 representing the most common form of dementia. In AD, the amyloid cascade hypothesis posits that amyloid-␤ (A␤), produced through the sequential proteolytic cleavage of the amyloid precursor protein (APP) by the ␤-and ␥-secretases, is a key molecule in initiating and propagating disease pathology including neurofibrillary tangle formation, neuronal cell loss, aberrant synaptic activity, and brain atrophy that lead to the clinically recognized symptoms of dementia (1). However, identification of the A␤ peptide 25 years ago has not yet led to the advent of a viable therapeutic strategy that can slow or halt the progression of AD. Recent studies have revealed new complexities in the proteolytic processing of APP, including the identification of novel secretases which generate APP metabolites that accumulate in the brains of AD patients and may contribute to the synaptic dysfunction observed in the disease. In addition, numerous proteins are being identified that interact with APP, modulating its proteolysis and A␤ production. These new APP secretases and metabolites, along with the APP interactors, may present novel therapeutic targets that are independent of direct modulation of the canonical secretases and that will need to be considered when evaluating the results from current A␤-directed therapies. In this Minireview, we summarize the recent developments in APP proteolysis focusing on the novel secretases, APP interactors, and APP metabolites that are impacting on our understanding of both APP biology and the neurodegenerative disease process. The Canonical ␣-, ␤-, and ␥-Secretases and APP FragmentsThe generally accepted model of APP proteolysis is that APP is processed by one of two distinct proteolytic pathways (Fig. 1A). In the amyloidogenic pathway, ␤-secretase, the ␤-site APP-cleaving enzyme 1 (BACE1), cleaves APP within the ectodomain and liberates a soluble proteolytic fragment, termed soluble APP␤ (sAPP␤), primarily in the endosomal system from the transmembrane APP holoprotein (2). The remaining C-terminal membrane-bound APP fragment, CTF␤, is subsequently cleaved by the presenilin (PS)-containing ␥-secretase multisubunit complex to liberate the A␤ peptide and the APP intrace...

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Neuroprotective role of MMP-9 overexpression in the brain of Alzheimer's 5xFAD mice

Cited by 64 publications

References 76 publications

Overexpression of matrix metalloproteinase-9 (MMP-9) rescues insulin-mediated impairment in the 5XFAD model of Alzheimer’s disease

Overexpression of matrix metalloproteinase-9 (MMP-9) rescues insulin-mediated impairment in the 5XFAD model of Alzheimer’s disease

Conditioned medium from the stem cells of human dental pulp improves cognitive function in a mouse model of Alzheimer’s disease

A Greek Tragedy: The Growing Complexity of Alzheimer Amyloid Precursor Protein Proteolysis

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