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Astrocytes as regulators of neuronal autophagy in ageing brain

Primary Supervisor: Dr Yuriy Pankratov, School of Life Sciences

Secondary supervisor: Professor Ioannis Nezis

PhD project title: Astrocytes as regulators of neuronal autophagy in ageing brain

University of Registration: University of Warwick

Project outline:

The increasing proportion of elderly people in the population means that age-related cognitive decline is a major contributor to the rising costs of medical and social care. There is accumulating evidence linking brain longevity to molecular mechanisms of cellular homeostasis, in particular the process of autophagy. Autophagy is a complex mechanism of degradation of potentially harmful substances inside the cells. Enhancement of autophagy in brain cell is viewed nowadays as a most perspective strategy to slow down the progression of age-related brain disorders. Nevertheless, cellular and molecular mechanisms that underlie the role of autophagy in synaptic dynamics and cognitive function, remain largely unexplored.

There is a growing understanding in the research field that aging-related brain diseases can be fully understood only in the context of complex cellular networks responsible for brain homeostasis. Recent studies, including our work, have shown crucial importance of interactions between neurons and astrocytes for brain longevity. Our preliminary results show that brain astrocytes can induce neuronal autophagy by releasing the endogenous autophagy modulator spermidine. These results have tied together the anti-ageing effects of autophagy, synaptic plasticity and astrocytes and highlighted a novel mechanism of glia-neuron interactions. However, the roles for these mechanisms in cognitive function and brain longevity remain to be studied.

THE OVERALL AIM of the project is to study the astrocyte-driven regulation of autophagy in brain neurons and its impact on synaptic transmission and plasticity across a lifetime.

In particular, we shall test the hypothesis that brain astrocytes regulate neuronal autophagy by release of spermidine and thereby improve synaptic dynamics and cognitive functions. We shall also elucidate how decline in synaptic plasticity and memory can be ameliorated via glia-mediated induction of autophagy in brain cells by caloric restriction and physical exercise.

SPECIFIC OBJECTIVES are to investigate:
1) key role for neuronal autophagy in the beneficial effects of caloric restriction and exercise on synaptic transmission, plasticity and memory;
2) impact of astrocytes on diet-induced induction of autophagy in the brain neurons;
3) the age- and diet-related changes in release of autophagy modulators from brain astrocytes.

METHODOLOGY: the project will use state-of-the-art methodologies to analyze aged brain tissue, including advanced patch-clamp recordings and statistical analysis of synaptic currents, fluorescent imaging in the brain slices of old animals and detection of autophagy using a variety of cellular and molecular markers and techniques. In particular, we will compare the basal synaptic transmission and long-term synaptic plasticity in mice with inducible neuron-specific impairment of autophagy (Beclin1-KO mice) with their wild-type counterparts. We will also use transgenic mice expressing fluorescent ratiometric autophagy probe (CAG-RFP-EGFP-LC3 line), as well as analysis of autophagosome formation by electron microscopy to monitor the changes in neuronal autophagy.

References:

  1. Tomoda, T., Yang, K., and Sawa, A. (2020). Neuronal Autophagy in Synaptic Functions and Psychiatric Disorders. Biological Psychiatry 87, 787-796.
  2. Lalo, U., and Pankratov, Y. (2021). Astrocytes as Perspective Targets of Exercise- and Caloric Restriction-Mimetics. Neurochemical Research. PMID: 33677759
    DOI: 10.1007/s11064-021-03277-2

BBSRC Strategic Research Priority: Understanding the Rules of Life: Neuroscience and behaviour & Structural Biology & Integrated Understanding of Health: Ageing & Diet and Health

Techniques that will be undertaken during the project:

  • Electrophysiological recordings and statistical analysis of synaptic currents and potentials in neurons of brain slices of transgenic mice
  • Multi-photon fluorescent microscopy
  • Electron microscopy
  • Immunocytochemistry

Contact: Dr Yuriy Pankratov, University of Warwick