טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentAvramovich-Tirosh Yael
SubjectNeuroprotective/Neurorescue Mechanisms and Processing
of the Alzheimer's Disease APP by Novel Multi-
Functional Iron-Drugs
DepartmentDepartment of Medicine
Supervisor Professor Emeritus Moussa Youdim
Full Thesis textFull thesis text - English Version


Abstract

A consistent observation in Alzheimer’s disease (AD) is a dysregulation of metal ions homeostasis and consequential induction of oxidative stress. The concept of iron chelators for clinical use in neurological disorders lead our group to develop non-toxic, lipophilic, brain permeable multifunctional compounds with iron chelation properties for neurodegenerative diseases. Based on a multimodal drug design paradigm, we incorporated the neuroprotective propargylamine moiety of the anti-Parkinson drug, rasagiline, into the antioxidant-iron chelator moiety of our prototype iron chelator, VK28. Among these novel compounds, M30 was found to confer potential neuroprotective effects in vitro and in various preclinical neurodegenerative models.

In the present study, M30 was found to attenuate amyloid b(25-35) (Ab(25-35)) protein neurotoxicity and decrease apoptosis of SH-SY5Y cells in a neurorescue, serum deprivation model. Also, M30 induced the outgrowth of neurites, triggered cell cycle arrest in G0/G1 phase and enhanced the expression of growth associated protein-43 (GAP-43) protein. Furthermore, M30 markedly reduced the levels of cellular amyloid precursor protein (APP) and b-C-terminal fragment (b-CTF) and the levels of the amyloidogenic Ab peptide in the medium of SH-SY5Y cells and CHO cells stably transfected with the APP ‘Swedish’ mutation. Levels of the non-amyloidogenic soluble APPa and a-CTF in the medium and cell lysate, respectively were coordinately increased. Additionally, the novel iron chelator drug suppressed translation of a luciferase reporter mRNA via the APP 5'UTR sequence.

M30 significantly increased the expression of hypoxia-inducible factor-1a (HIF-1a) mRNA and protein and HIF-1a-dependent genes (e.g. vascular endothelial growth factor (VEGF), erythropoietin, enolase 1, p21) in rat cultured primary cortical neurons. Finally, M30 enhanced protein kinase B (Akt), glycogen synthase kinase 3b (GSK-3b), protein kinase C (PKC) and extracellular signal-regulated protein kinase 1/2 (Erk1/2) signaling phosphorylation in rat primary cortical neurons and inhibited the phosphorylation of the microtubule-binding protein, Tau.

These properties, together with its brain selective MAO inhibitory and propargylamine- dependent neuroprotective effects, suggest that the novel multimodal M30 might serve as an ideal drug for neurodegenerative disorders, such as Parkinson’s and AD.