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

Abstract

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.

Conditional BDNF delivery from astrocytes rescues memory deficits, spine density and synaptic properties in the 5xFAD mouse model of Alzheimer disease

“…A significant body of evidence indicates that enhancement of the BDNF delivery or function via activation of its high-affinity receptor TrkB could be a promising therapeutic approach in AD (Allen and Dawbarn, 2006;Ohno, 2012, 2015;Zhang et al, 2014;Kaminari et al, 2017). Based on our results, we propose that the use of engineered astrocytes could be an interesting means to achieve this objective.…”

“…Indeed, BDNF plays important roles in neural survival and synaptic plasticity (Lynch et al, 2008). In line with this, BDNF is reduced early in the course of the disease in transgenic mouse models of AD (Kaminari et al, 2017), and TrkB deletion accelerates and worsens the phenotype of these mice (Devi and Ohno, 2015), whereas TrkB agonists improve it (Devi and Ohno, 2012;Zhang et al, 2014). Alterations in the BDNF-TrkB system could account for memory deficits, neuronal cell death, and synaptic plasticity alterations observed in AD (von Bohlen Und Halbach and von Bohlen Und Halbach, 2018).…”

The pharmacological perturbation of brain zinc impairs BDNF-related signaling and the cognitive performances of young mice

“…MMP-9 contributes to learning, memory and neuronal plasticity by promoting the spine remodelling and immobilization of ionotropic receptors that occur upon long-term potentiation (LTP) stimulation 26 , 27 . In preclinical models of Alzheimer’s disease (AD), the functional overexpression of MMP-9 increases the brain levels of mBDNF and prevents the development of AD-related cognitive deficits 28 , 29 . MMP-9 is structurally characterized by a 3-histidine zinc-binding catalytic motif (His-Glu-Xaa-Xaa-His) and requires zinc (Zn 2+ ) to exert its proteolytic activity 30 .…”

Characterization of Matrix Metalloprotease-9 Gene from Nile tilapia (Oreochromis niloticus) and Its High-Level Expression Induced by the Streptococcus agalactiae Challenge

“…We deduce that MMP-9 expression varies from different tissues and different time points between hosts and pathogens, and the instability of MMP-9 mRNA or inhibitors may change it [4]. In addition, overexpression of MMP-9 reduces cell apoptosis in mice [40]. These results indicate that NtMMP-9 has a positive role in the immunological regulation of Nile tilapia.…”