Gleeson- Heneka collaborative projects
Melbourne subproject:
to be announced
Dept of Biochemistry
& Molecular Biology
Email Paul
Bonn subproject:
The cell biology of Alzheimer’s disease; amyloid-ß production and neuroinflammatory responses
Dept of Neurology
Clinical Neurosciences
Unit
Email Michael
PhD Student
Dept of Neurology
Clinical Neurosciences
Unit
Alzheimer’s disease (AD) is a chronic, multifactorial neurodegenerative disorder and the most prevalent dementing disease. Pathological characteristics of AD include extracellular deposition of β-amyloid (Aβ) and intracellular neurofibrillary tangles, believed to play an important role in the pathogenesis of this disease. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors, which either regulate endosomal sorting events or the inflammatory reaction. The APOE gene has been identified as the most significant genetic risk factor for late onset AD. The apoE protein is believed to affect AD pathogenesis through a variety of mechanisms, including effects on the blood brain barrier, the innate immune system, synaptic function and the accumulation of Aβ. Aβ deposition and abnormal tau protein cause loss of synaptic function, mitochondrial damage, activation of microglia, resulting in neuronal death. It is becoming increasingly evident that neuroinflammation mediated by primed microglia cells also contribute to AD pathogenesis, making neuroinflammation another important hallmark of AD pathology.
The project aims to investigate the influence of neuroinflammation on Aβ production, in particular the impact of inflammatory cytokines on intracellular convergence of BACE and APP and Aβ production in primary neurons. This will be performed by investigating the impact of immunostimulated microglia supernatants on BACE1 and APP trafficking and Aβ production in cultured primary neurons.
Mutant microglia for human AD risk genes will be obtained from APOE target replacement mice (APOE 2/3/4) and compared to wild type microglia in terms of function before and after immunostimulation. Supernatants of immunostimulated microglia will be used to identify and compare inflammatory cytokines, complement factors and ROS. Primary cortical neurons will then be subjected to these supernatants and APP processing, BACE1 promotor regulation, transcription and expression will be analysed. Furthermore, APP and BACE1 trafficking will be studied in the presence and absence of the described supernatants.