Investigating alterations in autophagy in Alzheimer’s Disease patient derived fibroblasts

Dr Gemma Lace-Costigan, (

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. AD is pathologically characterised by intracellular aggregations of abnormally phosphorylated tau protein and the formation of extracellular beta-amyloid (Aß) plaques. Abnormal accumulations of protein are also seen in other neurodegenerative disorders including Parkinson’s disease and Huntington’s Disease, with the severity of pathology often being associated with increased cognitive impairment.

The accumulation of pathogenic proteins in AD has been linked to a defective autophagic pathway, which normally functions to clear abnormal or defective proteins from the brain. Though disrupted autophagy in AD has been reported in animal models and in human autopsy tissue, it is unclear whether autophagic alterations extend to peripheral cells such as skin-derived fibroblasts. Many of the neuronal changes reported in AD, such as the accumulation of toxic proteins, increased oxidative stress and mitochondrial abnormalities have also been reported in fibroblasts derived from AD patients. Fibroblasts are an easily accessible tissue source available from living AD patients. The study of fibroblasts allow the investigation of the progression of molecular events across various disease stages, with fewer ethical and methodological issues than human post-mortem or animal tissue use.

This project will investigate alterations in autophagy in AD patient fibroblasts by assessing protein and mRNA levels of key regulators and markers this pathway. Drugs and siRNA will be used to target specific proteins/genes of interest and the impact of these therapeutic interventions on more well defined molecular AD changes such as tau, Aß and oxidative stress levels will be assessed. The student will attain experience in tissue culture, immunocytochemistry, western blotting, RT-PCR, enzyme assays and siRNA gene silencing.

This project could potentially identify a peripheral diagnostic biomarker of AD as well as a new target for therapeutic intervention. It is anticipated that the results of this project will be published across several high impact peer-reviewed scientific papers (Qualis A1 journals) and the student will be expected to present research findings at both national and international conferences.

T: +44 (0)161 295 5111