Neuroscience research study

We invite applications to study for MSc by Research or PhD.

Investigating GABAergic downregulation as a candidate causal link between mid-life hearing loss and Alzheimer’s disease

Vacant until filled

Hearing loss is the leading mid-life risk factor for dementia. Changes in the brain after mid-life hearing loss (the most common type of hearing loss) may cause Alzheimer’s disease (the most common type of dementia).

Mid-life hearing loss causes a reduction in the amount of the neurotransmitter GABA in parts of the brain crucial for hearing. We have developed evidence that ageing causes reductions in GAD65 (which catalyses the generation of GABA for neurotransmission) in auditory nuclei, using a new rat model of age-related hearing loss and Alzheimer’s disease.

We have also developed a method that allows us to measure changes in pre-synaptic GABA using super-resolution confocal microscopy.

This project will investigate whether noise-induced hearing loss in mid-life is a direct cause of increased Alzheimer’s disease-like damage in a translatable rat model. These changes will be compared to human post-mortem brain samples.

If successful, we will produce the first evidence that hearing loss causes dementia and validate a pre-clinical model that can be used to develop new therapies.

Contact us

To get further details and make an informal study enquiry, you can contact Dr Llwyd Orton.

Email Dr Orton

Investigate the role of the immediate early gene Arc/Arg3.1 in iPS differentiated neurons from patients with Alzheimer’s disease

Vacant until filled

Imbalance in hippocampal neuronal activity is believed to underlie early cognitive decline observed in ageing and in neurodegenerative conditions such as Alzheimer’s disease (AD). However, the precise mechanism underlying these early changes are not well characterised.

A potential candidate involved on this process is the immediate early gene Arc/Arg3.1. It is well-established that an increase in neural network activity induce transcription and translation of Arc/Arg3.1.

In turn, increased levels of Arc/Arg3.1 expression facilitate endocytosis of synaptic glutamatergic AMPA receptors to reduce synaptic transmission and maintain the balance of the network activity.

Therefore, changes in levels of Arc/Arg3.1 expression may be associated with early pathological changes in AD. Although the mechanism by which increased neural activity regulates Arc/Arg3.1 is well-characterised using rodent models, not much information is available about Arc/Arg3.1 function in human cells.

This project will address pivotal questions about Arc-Arg3.1 function and interacting partners regulating AMPA receptor trafficking in neurons differentiated from human embryonic stem cells (ESCs) and inducible pluripotent stem cells (iPSCs) obtained from AD patients.

You will learn a wide range of approaches that are fundamental in biomedical research including cell culture and the use of protocols to differentiate ESCs and iPSCs into neurons, immunocytochemistry combined with confocal imaging, techniques in molecular biology and biochemical methods of sample preparations.

Supervisors

Prof Sonia Correa-Muller - who uses a wide range of approaches in cell and molecular biology combined with electrophysiology and behavioural approaches to study Arc/Arg3.1 function
Dr Baoqiang Guo - who is an expert in using protocols to differentiate human iPSCs

Contact us

To get further details and make an informal study enquiry, you can contact Prof Sonia Correa-Muller and Dr Baoqiang Guo.

Epigenetic biomarkers in early stages of Alzheimer’s disease

Vacant until filled

Epigenetic studies performed with post mortem brain tissue from Alzheimer disease’s (AD) patients have revealed genes with altered DNA methylation.

However, as these studies were performed using post-mortem tissue it is not clear at which stage of the disease these changes occurred. To determine epigenetic changes (DNA methylation) in brain tissue at the different stages of AD we will use two different approaches.

We will measure DNA methylation using a genome-wide approach in cerebrospinal fluid (CSF) and in brain-derived exosomes (BDE) isolated from blood samples. Exosomes are vesicles secreted by cells containing RNA, proteins and DNA. Exosomes secreted from the brain (or BDE) can be isolated from blood samples what facilitates the sample collection. The methylated genes found in these analyses will be further investigated using in silico tools to discover pathways involved in the development of AD.

As a research student, you will perform epigenetic studies using CSF and blood samples collected from early AD, mild cognitive impairment (MCI), prodromal AD and control subjects to determine whether DNA methylation is a risk factor associated with the occurrence of AD.

You will learn a wide range of techniques including:

1. An Epigenome-Wide association study (EWAS) study will be performed in CSF and BDE to analyse:

50 AD cases
50 MCI patients
50 patients with subjective memory complaints (SMC) in the preclinical phase of the AD but positive for AD biomarkers (CSF or PET imaging)
50 controls with the EPIC-Infinium BeadChip (Illumina) that quantitatively measures 850,000 methylation genome regions

This analysis will identify changes in methylation associated with each stage of the disease.

2. Data obtained from EWAS will be integrated with metadata analysis from Genome-Wide Association published data using Mixomics and other platforms.

3. Using the available in silico functional data, we will determine which genes show altered RNA expression due to the changes in DNA methylation. We will then use a drug-repositioning approach to determine whether there are drugs or a combination of drugs that can modulate the methylated genes.

Supervisors

Contact us

To get further details and make an informal study enquiry, you can contact Prof Jurek Krupinski and Prof Sonia Correa-Muller.

Self-funded PhD Research Project

Investigate the mechanism by which CD33 short isoform expressed in microglia/macrophages is a protective factor for late onset of Alzheimer’s disease

Manchester Metropolitan University, Centre for Bioscience, Faculty of Science and Engineering

About the project:

Alzheimer’s disease (AD) affects nearly 50 million people worldwide, and currently no fundamental and effective disease-targeting treatment is available. Confronting the failure of anti-amyloid-β or tau-based therapies, discovery of new targets has become an unmet necessity for AD prevention and therapy. Increasing amount of evidence suggests that microglia, the brain’s immune cells, play critical role in maintaining homeostasis and sense pathological changes by continuously surveying the parenchyma with highly motile large processes. A number of genes were found to be highly relevant to late-onset sporadic AD (LOAD), the most common form of AD. It has been noted that most of these genes are involved in microglial functioning. Polymorphism of microglial receptors such as CD33 and triggering receptors expressed on myeloid cells 2 (TREM2) have been found strongly associated with the possibility of developing AD. For example several genome-wide association studies (GWAS) identified single nucleotide polymorphisms (SNPs rs3865444C) in CD33 were related with LOAD susceptibility, however, the rs12459419T allele correlates with decreased AD susceptibility, which was further confirmed by A systemic meta–analysis of AD GWAS datasets. The SNP (rs12459419) located within the second exon, leading to increased production of a short isoform known as human CD33m[1-5]. On the contrary, the common rs12459419C allele with a long isoform of CD33 (CD33M) correlates with increased AD susceptibility. However, the underlying mechanism by which the short isoform CD33m plays a protective role in preventing the LOAD by increased phagocytosis of amyloid beta (Aβ) is unclear. In an attempt to therapeutically target CD33 in a way that effectively mimic the AD protection revealed by GWAS studies, a better understanding of the roles played by these two isoforms in microglia/macrophage is needed to mimic the in vivo niche with an in vitro human microglia model.

Aim: To elucidate the underlying molecular mechanism by which expression of human short CD33 isoform in microglia/macrophage correlates with clearance of amyloid beta using human iPSC-derived microglia/macrophage in vitro 2-D induced microglia and 3-D matrigel induced microglia model.

During the studentship, the student will learn a wide range of techniques such as:

1) iPSCs cultures, maintenance and directed differentiation of iPSCs into microglia/macrophage.

2) Microglia/macrophage 2-D iMicroglia and 3-D matrigel-iMicroglia model. U937WT and CD33- mutants-differentiated macrophages will be grown in 6-well culture plates coated with Matrigel in the presence and absence of Aβ; In 3D-model, U937WT and CD33-mutants-differentiated macrophages will be embedded in 1:3 diluted Matrigel in the presence and absence of Aβ.

3) Immunocytochemistry combined with confocal imaging, biochemistry, flow-cytometry, holoimage analysis and RT-qPCR. The project will be supervised by Dr Guo and Professor Corrêa-Müller from Centre of Bioscience at Manchester Metropolitan University and Professor Xianwei Zheng from Beijing Rehabilitation Hospital Affiliated to National Research Centre for Rehabilitation Technical Aids, Ministry of Civil Affairs of China.

How to Apply: Enquiries and request for further information should be addressed to:

Dr Baoqiang Guo, Email: B.guo@mmu.ac.uk
Professor Sonia Correa-Muller, Email: s.correa-muller@mmu.ac.uk
Professor Xianwei Zeng, Email: Zengxwei@163.com 2

References:

1. Carrasquillo MM, Belbin O, Hunter TA, Ma L, Bisceglio GD, Zou F, Crook JE, Pankratz VS, Sando SB, Aasly JO, Barcikowska M, Wszolek ZK, Dickson DW, Graff-Radford NR, Petersen RC, Passmore P, Morgan K, for the Alzheimer’s Research UK (ARUK) consortium, Younkin SG. Replication of EPHA1 and CD33 associations with late-onset Alzheimer’s disease: a multi-Centre case-control study. Mol Neurodegener. 2011;6(1):54. https://doi.org/10.1186/1750-1326-6-54.

2. Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM, Abraham R, Hamshere ML, Pahwa JS, Moskvina V, et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet. 2011;43(5):429–35. https://doi.org/10.1038/ng.803.

3. Naj AC, Jun G, Beecham GW, Wang LS, Vardarajan BN, Buros J, Gallins PJ, Buxbaum JD et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat Genet. 2011;43(5):436–41. https://doi.org/10.1038/ng.801.

4. Malik M, Simpson JF, Parikh I, Wilfred BR, Fardo DW, Nelson PT, Estus S. CD33 Alzheimer’s risk-altering polymorphism, CD33 expression, and exon 2 splicing. J Neurosci. 2013;33(33):13320–5. https://doi.org/10.1523/JNEUROSCI.1224-13.2013.

5. Bhattacherjee A, Jung J, Zia S, Ho M, Eskandari-Sedighi G, Laurent CDS, McCord KA, Bains A, Sidhu G, Sarkar S, Plemel JR. Macauley MS. The CD33 short isoform is a gain-of-function variant that enhances Aβ1–42 phagocytosis in microglia. Mol Neurodegeneration 16, 19 (2021). https://doi.org/10.1186/s13024-021-00443-6