Lei, P. (2012). Ironing out the involvement of tau protein in neurodegenerative diseases. PhD thesis, Medicine, Dentistry & Health Sciences - Pathology, The University of Melbourne.


Abstract Tau protein has been extensively implicated in Alzheimer’s disease (AD), Parkinson’s disease (PD), and other neurodegenerative diseases,,, Brain iron accumulation is a cooccurred pathological feature of many tauopathies and hypothesized to contribute to neurodegeneration by engendering oxidative stress. It is currently unknown what, if any, link exists between tau and iron accumulation in these diseases. The aims of this thesis were to understand, 1) how does tau participate in neurodegeneration; 2) whether tau is involved in brain iron homeostasis; and 3) whether this putative interaction contributes to neurodegeneration in the tauopathies.
The normal function of tau has remained elusive... These mice, however, have not extensively been investigated older than 7-months of age. Therefore, an analysis of aged (12-24 months) tau KO mice was undertaken in this thesis. Aged tau KO mice exhibited features of dementia (reduction of brain wet weight, neural cortical atrophy and cognitive impairment) and parkinsonism (L-DOPA responsive motor disability, neuron loss in substantia nigra [SN], striatal dopamine reduction and dopaminergic terminal atrophy). ...
Iron accumulation was observed in the brains of aged tau KO mice. ..Therefore, tau depletion (as also observed in AD and PD) may engender pro−oxidant neuronal Fe2+ elevation preceding neurodegeneration.

The mechanism of tau-induced iron accumulation was investigated in this thesis, which revealed a previously overlooked functional interaction between tau and the AD-implicated, amyloid precursor protein (APP). Immature APP undergoes several post-translational modifications before it is transported to the cell surface where it functions as an iron-export ferroxidase. Deletion of tau decreased the presence of mature APP presented on the cell surface which prevented the efficient neural export of iron. Disrupted trafficking of APP could therefore explain iron accumulation in the tau KO mouse, and in diseases exhibiting soluble tau reduction.

Tau reduction may also be pharmacologically induced by the...lithium.... In this thesis, lithium chloride caused intracellular iron accumulation.. This accumulation was abolished when treated to neurons that lacked tau or APP, demonstrating that lithium-induced iron accumulation was mediated by disruption to the tau-APP axis presented in this thesis. Lithium treatment has been previously associated with Parkinsonian side-effects; in this thesis, oral administration of lithium (in an upper-therapeutic range) to background mice caused brain-iron accumulation accompanying Parkinsonian neurodegeneration (motor disability, neuronal loss in SN, dopamine reduction in striatum). Given these striking findings, an MRI-analysis of iron in the brains of individuals who were treated with lithium (for three months) was performed, which revealed evidence of reversible iron elevation in selected regions upon treatment.
This thesis, which investigated the function of tau and its loss-of-function phenotype, concluded that the reduction of soluble tau primes neurons for age-dependent neurodegeneration by decreasing APP-mediated iron export. ...

http://dtl.unimelb.edu.au:80/R/693XP...s_handle=GUEST