Alzheimer's and Parkinson's Disease Laboratory
Head of laboratory
Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative disorders in humans. They are characterised by insoluble protein deposits; beta-amyloid plaques and tau-containing neurofibrillary lesions in AD, and alpha-synuclein-containing Lewy bodies in PD. As a significant percentage of patients have clinical and pathological features of both diseases, the patho-cascades of the two diseases might overlap.
Approximately 245,400 Australians are currently diagnosed with dementia, causing a huge socio-economic impact. With an aging population, numbers are projected to increase to 1.3 million cases by 2050, making dementia a major health threat in the near future. Of all forms of dementia, Alzheimer’s disease is the most prevalent, and it is characterised by a progressive decline of cognition that is associated with deposition of proteins in brain. Amyloid-β (Aβ) forms extracellular plaques, while hyperphosphorylated tau forms intracellular neurofibrillary tangles. To date, diagnostic tools are limited and there is no cure for Alzheimer's disease.
The research of A/Prof Lars Ittner and his team aims at identifying pathological mechanisms underlying neurodegeneration in Alzheimer's disease and other forms of dementia, and then further translate these findings into novel therapies to battle these devastating disorders. This cutting-edge research involves the latest transgenic in vivo technologies, complemented by novel neuronal cell culture systems.
Alzheimer’s disease (AD) is characterized by amyloid-beta (A&beta) and tau deposition in brain. It emerges that A&beta toxicity is tau-dependent, although mechanistically this link remains unclear. Here we show that tau, known as axonal protein, has a dendritic function in post-synaptic targeting of the Src kinase Fyn, a substrate of which is the NMDA receptor (NR). Missorting of tau in transgenic mice expressing truncated tau (Δtau) or absence of tau in tau-/- mice both disrupt post-synaptic targeting of Fyn. This uncouples NR-mediated excitotoxicity and hence mitigates Aβ toxicity. Δtau expression and tau-deficiency prevent memory deficits and improve survival in Aβ-forming APP23 mice, a model of AD. These deficits are also fully rescued with a peptide that uncouples the Fyn-mediated interaction of NR and PSD-95 in vivo. Our findings suggest that this dendritic role of tau confers Aβ toxicity at the post-synapse with direct implications for pathogenesis and treatment of AD (for more details: Ittner et al., Cell, 2010).