Iron export failure in the neurodegenerative disease: Alzheimer´s, Parkinson´s and dementia

• Applicant: Abdel Ali Belaidi, Ph.D.
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Biochemistry ; Sensory and Behavioural Biology
• Term: from 2013 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 251692664

Alzheimer disease (AD) Parkinson disease (PD) and tauopathies are intractable brain diseases that cause enormous burdens on our health care systems. AD is the leading cause of dementia in aging and is characterized by two pathological hallmarks: the accumulation of aggregated amyloid beta (A-beta) and excessively phosphorylated Tau proteins. AD, PD and taupathies are not necessarily nosologically separate. Indeed, AD is a risk factor for PD, and PD is almost invariably complicated by cognitive loss. Furthermore, tau mutations induce both dementia and PD, and tau is a risk allele in common for AD and PD. Neuronal iron accumulation is pathologically common for cortex in AD, substantia nigra in PD, and affected brain regions in all tauopathies. The host institution have made strong inroad in understanding the importance and the mechanism that cause zinc accumulation in AD, PD and the taupathies and have been instrumental in developing a therapeutic approach that targets abnormal metal enrichment in amyloid. Although, multiple large-scale clinical trials for AD targeting A-beta have failed to meet their clinical endpoints, three small clinical trials targeting metal interactions with A-beta all shown benefits for patients. The current proposal capitalizes on recent publications of the host institution in Cell and Nature Medicine, as well as recent findings that (i) Tau and the amyloid precursor protein (APP) play major physiological roles in the export of neuronal iron, (ii) the dysregulation of Tau or APP in AD and PD leads to toxic intra-neuronal iron accumulation, (iii) dysregulated brain iron metabolism (including APP and ceruloplasmin) is represented in the periphery in AD and PD. Here, the proposed research project aims to understand the significance of these changes in AD and PD using multiple experimental approaches and available animal models (APP-/-, CP-/- and tau-/-), which may contribute to the development of new therapeutic approaches towards those diseases

• DFG Programme: Research Fellowships
• International Connection: Australia
• Host: Professor Ashley Bush