How does stress regulate tau-associated synaptic function?

Stress is a normal daily experience, and is ordinarily a useful physiological response. However, prolonged, chronic stress can have a significant negative impact on health, and is thought to underlie and contribute to the onset of several diseases. At the cellular level, stress hormones can change neuronal function, but our understanding of the mechanisms underlying these effects is currently limited. Our overall objective is to examine how stress contributes to ageing in the brain. More specifically, we're interested in determining how dynamic communication between nerve cells can be dysregulated by stress hormones. Our project focuses on the role of a protein named tau, and how it might mediate the impairing effects of stress. Tau has well-established roles in several neurological pathologies, and our preliminary investigation has revealed a possible causal relationship between stress hormones and the aberrant regulation of tau protein in neurons. Our proposed research is of a fundamental, basic science in foundation. However, findings from our study could well improved our understanding of the molecular mechanisms underlying stress hormone-dysregulation of the central nervous system, and may shed new light on why stress might contribute to ageing.

The project is designed to characterize the mechanisms relating stress with aberrant synaptic plasticity, specifically the role of stress hormone in the initiation of the synapse death signal pathway (SDP) and subsequent changes in gross spine anatomy, with a particular focus on the involvement of tau hyperphosphorylation (pTau; tauopathy). The first objective is to identify how the glucocorticoid (GC)-induced pTau in CA1 neurons in the hippocampus contributes to the impairment of synaptic plasticity. The specific phospho-residues, from a selection chosen for their relevance to synapse elimination pathways, will be mutated into phospho-dead forms of tau, and then expressed in cultured organotypic hippocampal slices. The capacity for GCs to then impair synaptic plasticity will be examined, allowing us to determine the phosphocode relevant to GC-mediated synapse ageing. We will also examine the contribution of known SDP kinases and proteases to these events, with a specific focus on the GSK-3beta signalling pathway. The second objective is to examine how the GC-induced pTau regulates the protein machinery that is responsible for AMPAR endocytosis. We will examine the role of GC-induced pTau in the regulation of the interactions between PICK1 and GluA2 AMPARs, and GRIP and GluA2 AMPARs, pivotal mechanisms in the endocytosis of AMPARs. We will then move on to examine a potential role of key tau interacting protein PACSIN in pTau-mediated AMPAR endocytosis. Finally, we will test the hypothesis that the dysregulation of synaptic plasticity by GC-induced pTau is concomitant with changes to synaptic integrity. Here we will examine dendritic morphology by assaying spine size and density using two-photon microscopy, following exposure to GCs.

Academic beneficiaries: The beneficiaries from this research depend on the success of the study. At the least, our integrative approach will provide novel and fundamentally important information for a range of basic scientists who are actively pursuing research concerning stress and biological ageing. Specifically, it is yet to be fully understood how the environment affects our biological systems and leads to brain ageing. Accordingly, our proposal could make a very novel and worthy contribution to the understanding of how biological stress affects synaptic integrity and its fate between survival and death. Therefore, the academic beneficiaries include a wide-range of researchers in the science community, particularly those involved with synaptic biology and neuronal function.

Commercial beneficiaries: Since the proposed study is seeking a fundamental understanding of synapse biology, no immediate links with the commercial sector are proposed. However, there is potential for translation into enterprise. Findings from this proposed study, for instance the effect of stress on biological mechanisms of brain ageing, are to be presented during at least two international conferences. Furthermore, a high-priority is to publish work in high-impact journals. This should give the commercial sector opportunity to engage with findings generated from this work. There is a growing population of ageing-related neurodegenerative disease, and most cases are progressive diseases. Unfortunately, there is no effective therapeutic strategy for these progressive ageing-related diseases. There is slow progress in terms of R&D from the industry sector due to high-risk/lack of understanding of biological mechanisms of the ageing neuron. This work aims to identify novel mechanisms underlying synaptic function, which could have potential in the identification of new therapeutic targets for diseases related with ageing mediated progressive synaptic impairment. Thus, outcomes of this study will provide a platform for new pathways of 'academic-industry joint research environments', and facilitate therapeutic target discovery.

Public sector beneficiaries: We aim to understand how stress contributes to the ageing process. This is an issue of paramount importance in our highly-industrialised society, where the daily stress is taken as norm, yet our understanding of the long-term effects of this are primitive. Our study has the potential to reveal fundamental biological mechanisms that underpin the relationship between stress and accelerated ageing, information that could well inform both future study and therapeutic agenda. More critically, revealing a causative link between stress and the acceleration of brain pathology could well lead to a fundamental reassessment of the dangers of chronic and permissive stress, which would inevitably have an impact on a societal level. Providing better health outcomes in ageing is clearly of significant importance in a society that is experiencing, and will continue to experience for the foreseeable future, an increasing proportion of elderly persons in the population. Unfortunately, there is no effective solution to stop ageing-related progressive neuronal diseases, which in most cases require long-term care. Therefore, it impacts individual families as well as society. Public sector beneficiaries also include members of the public through public engagement events organised by the University, academic science community and media. Public events are regularly held to inform and educate the general public in research undertaken by the University. Further, students will also benefit from the research - the applicants actively participates in school visits to explain research undertaken, and often supervises students who chose to perform work experience in the laboratory. These activities are very important to keep stable and continuation of research for the long-term.