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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.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disease and is nowadays turning to slow pandemic, due to its high prevalence of occurrence in the elderly population worldwide[1]
When IRS1 is phosphorylated at Tyrosine residues the insulin pathway is activated, whereas when it is phosphorylated at Serine residues its activation is inhibited, inhibiting the insulin receptors (IRs)-mediated survival signaling
Insulin survival pathway impairment caused by Aβ oligomers is considered a key event in the pathogenesis of AD during the early stages of the disease[17]
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disease and is nowadays turning to slow pandemic, due to its high prevalence of occurrence in the elderly population worldwide[1]. Oligomer-mediated insulin resistance occurs due to Aβ binding to the neuronal membrane surface, which results in the removal of the insulin receptors (IRs)[5, 12, 13] at the synaptic area and eventually to synapse loss. Insulin binds to its receptor and activates insulin substrate-1 (IRS1) via phosphorylation at Tyrosine residue 465 (pIRS1-Tyr[465]) This phosphorylation promotes the neurotrophic effects of insulin by activating cell survival Akt/PKB kinase (Akt). In early stages of AD, Aβ were reported to accumulate in post-synaptic areas leading to stimulation of pro-apoptotic pathways due to activation of the c-Jun N-terminal kinase (JNK) pathway; this results in phosphorylation of IRS1 at Serine residue 636 (pIRS1-Ser636), which renders IRS1 inactive and suppresses the stimulatory effect of insulin[17]. Stimulation of the insulin signaling pathway is a plausible mechanism of protection against Aβ oligomer-induced synapse loss
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