The Novel Multi-Target Iron Chelator, M30 Modulates HIF-1α-Related Glycolytic Genes and Insulin Signaling Pathway in the Frontal Cortex of APP/PS1 Alzheimer’s Disease Mice

Abstract

Increasing evidence suggests that dysregulation of brain insulin/insulin receptor (InsR) and insulin signaling cascade are associated with the pathogenesis of Alzheimer's disease (AD). Our group has designed and synthesized a series of multi-target iron chelating, brain permeable compounds for AD. One leading multi-target compound, M30 possesses the neuroprotective N-propargyl moiety of the anti-Parkinsonian, monoamine oxidase (MAO)-B inhibitor, rasagiline (Azilect®) and the antioxidant-iron chelating moiety of an 8-hydroxyquinoline derivative of the iron chelator, VK28. Positive outcomes for the behavioral/cognitive and neuroprotective effects of M30 were recently obtained in preclinical experimental studies, regarding pathological aspects relevant to ageing and AD. We report that chronic treatment with M30 (1 and 5 mg/kg p.o; three times a week for 9 months) significantly elevated cortical insulin and InsR transcript and protein expression, respectively and increased the phosphorylated form of glycogen synthase kinase-3β in the frontal cortex of amyloid precursor protein (APP) and presenilin 1 (PS1) double transgenic mice. In addition, M30 treatment upregulated the levels of hypoxia-inducible factor (HIF)-1α and expression of its target genes involved in glycolysis including, aldolase A, enolase-1 and glucose transporter-1 (Glut-1), in the frontal cortex of APP/PS1 mice. Treatment with M30 also lead to an increase in the hepatic protein expression levels of InsR and Glut-1 and lowered the increase in blood glucose levels following glucose tolerance test. The present findings indicate that the multifunctional iron chelating drug, M30 regulates major brain glucose metabolism parameters and thus, might be beneficial for AD, in which impaired neuronal insulin signaling and Glut expression have been implicated.

Metabolic changes and inflammation in cultured astrocytes from the 5xFAD mouse model of Alzheimer’s disease: Alleviation by pantethine

“…Astrocyte reactivity and glycolytic changes are known to be reversed by HIF-1α, whose up-regulation is generally associated with neuroprotective mechanisms against various insults [29,30,65]. HIF-1α expression is modulated by TCA metabolites that are involved in the regulation of prolyl hydroxylases (PHDs) [66,67] and proteasomal activity [68].…”

Neuroprotective effects of multifaceted hybrid agents targeting MAO, cholinesterase, iron and β‐amyloid in ageing and Alzheimer's disease

“…In addition, M30 was found to reduce brain iron accumulation and induce a significant reduction in a number of cerebral AD‐like phenotypes, such as APP, phospho‐APP, Aβ levels, Aβ plaques formation and aggregation, phospho‐tau and CDK‐5, as well as elevation of the levels of phospho‐PKB and phospho‐glycogen synthase kinase (GSK‐3β) (Kupershmidt et al ., ). Chronic treatment with M30 significantly elevated cortical insulin (Ins) and insulin receptor (InsR) mRNA and protein expressions, and increased the levels of cerebral HIF‐1α and the expression of HIF‐1‐target genes involved in glycolysis, including aldolase A, enolase‐1 and GLUT‐1 in APP/PS1 mice (Mechlovich et al ., ). Treatment with M30 also increased the hepatic protein expression levels of InsR and GLUT‐1 and attenuated the increase in blood glucose levels following glucose tolerance test in APP/PS1 mice (Mechlovich et al ., ).…”

“…Chronic treatment with M30 significantly elevated cortical insulin (Ins) and insulin receptor (InsR) mRNA and protein expressions, and increased the levels of cerebral HIF‐1α and the expression of HIF‐1‐target genes involved in glycolysis, including aldolase A, enolase‐1 and GLUT‐1 in APP/PS1 mice (Mechlovich et al ., ). Treatment with M30 also increased the hepatic protein expression levels of InsR and GLUT‐1 and attenuated the increase in blood glucose levels following glucose tolerance test in APP/PS1 mice (Mechlovich et al ., ). These findings indicate that iron chelating drugs, such as M30 may also affect impaired neuronal Ins signalling and GLUT‐1 expression, implicated in AD (Solano et al ., ; Salkovic‐Petrisic et al ., ), presumably through its regulation of glucose metabolism.…”

Multi-target iron-chelators improve memory loss in a rat model of sporadic Alzheimer's disease

“…Systemic treatment of transgenic (APP/presenilin 1) mice with M30 for 9 months, attenuated cognitive impairments, reduced cerebral iron accumulation, modulated glucose metabolism and reduced APP expression, Aβ accumulation and tau phosphorylation (Kupershmidt et al 2012;Mechlovich et al 2014a). …”