Role of extracellular vesicles in healthy aging of human brain

The neuronal cells of the human brain are central to maintaining normal cognitive and physiological functioning. Neurons are mostly post-mitotic with limited ability to regenerate and preservation of cellular health underlies healthy ageing. We have earlier shown that neuron-rich parts of normal human brain demonstrate a remarkable diversity at both the DNA (Sharma et al 2017) and the RNA levels (Paul et al, 2017). With the increasing life-span it is more important than ever to understand the molecular mechanisms that govern the healthy aging of neurons and how a dysfunction may trigger neurodegenerative disease conditions.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects approximately 500,000 people in the UK alone. AD is characterised by the abnormal accumulation of protein in neurons and subsequent cell death which leads to symptoms including memory loss, impaired cognition and personality changes. Though the main risk factor for developing AD is advancing age, there are numerous studies describing healthy ageing populations (eg the New England Centenarian Study) and so by comparing diseased and healthy ageing brain tissue we can understand which factors could contribute to healthy brain ageing.

Over the last decade, a body of research has supported a cellular ‘spread’ hypothesis which describes how AD pathogenesis seemingly spreads from cell to cell via neuroanatomical circuity (Lace et al, 2009, Pickett et al, 2017). A role for extra cellular vesicles (ECVs), particularly exosomes, in facilitating this disease propagation has been proposed, but the underlying mechanisms are unclear.

This study aims to understand the role of exosomes in AD and healthy ageing. The project will involve using cellular based models of healthy ageing and Alzheimer’s disease alongside human brain tissue from the Manchester Brain Bank. The successful applicant with develop laboratory expertise in a variety of methodologies including tissue culture, molecular biology, genetics, proteomics and cellular imaging.

Students will be expected to publish their findings in high quality journals and present their work in both national and international conferences.

Key references:

Paul D, Sinha AN, Ray A, Lal M, Nayak S, Sharma A, Mehani B, Mukherjee D, Laddha SV, Suri A, Sarkar C, Mukhopadhyay A. A-to-I editing in human miRNAs is enriched in seed sequence, influenced by sequence contexts and significantly hypoedited in glioblastoma multiforme. Sci Rep. 2017 May 26;7(1):2466. doi:10.1038/s41598-017-02397-6. PMID: 28550310.

Sharma A, Ansari AH, Kumari R, Pandey R, Rehman R, Mehani B, Varma B, Desiraju BK, Mabalirajan U, Agrawal A, Mukhopadhyay A. Human brain harbors single nucleotide somatic variations in functionally relevant genes possibly mediated by oxidative stress. Version 3. F1000Res. 2016 Oct 14 [revised 2017 Jan 1];5:2520. doi: 10.12688/f1000research.9495.3. eCollection 2016. PMID: 28149503.

Lace, G., Savva, G. M., Forster, G., De Silva, R., Brayne, C., Matthews, F. E., ... & Wharton, S. B. (2009). Hippocampal tau pathology is related to neuroanatomical connections: an ageing population-based study. Brain, 132(5), 1324-1334.

Pickett, E. K., Henstridge, C. M., Allison, E., Pitstick, R., Pooler, A., Wegmann, S., ... & Spires‐Jones, T. L. (2017). Spread of tau down neural circuits precedes synapse and neuronal loss in the rTgTauEC mouse model of early Alzheimer’s disease. Synapse, 71(6).