Alzheimer’s disease is the leading form of dementia and is a rapidly growing health issue internationally. While the hallmark pathological features of Alzheimer’s have been well characterized, there is still little understanding of the disease mechanisms that drive accumulation of amyloid peptide and tau microtubule protein in Alzheimer patient brains. New genetic susceptibility factors for late-onset Alzheimer’s disease (LOAD) have recently been uncovered in genome wide association studies (GWAS). Meta analysis of single nucleotide polymorphisms (SNPs) within 74,000 people (>23,000 AD cases), determined that SNPs in 20 loci were significantly associated with LOAD. Expression of a number of these genes (ABCA7, BIN1, CD33, CLU, CR1 and MS4A6A: with functions in amyloid peptide clearance, tau interactions, cholesterol and inflammation) is consistently altered in Alzheimer brains compared to cognitively normal individuals. It is unclear how LOAD risk gene expression is regulated in AD patients without SNPs in those loci.
Epigenetic changes are sequence-independent heritable traits acquired during an individual’s lifetime in response to environmental stimuli. Epigenetic modifications include chemical marks on histone proteins that package DNA into chromatin. Specific histone marks (such as acetylation, methylation, ubiquitination) direct gene expression or silencing. Alterations to histone acetylation have been extensively reported in Alzheimer’s and some LOAD risk genes can be regulated by epigenetic mechanisms. However, the environmental regulation of these epigenetic factors is not known. Large meta-analyses have now confirmed a loss of total brain copper in Alzheimer’s, and additional studies have shown that copper is an important regulator of epigenetic changes. This project investigates whether changes to copper regulation control expression of LOAD risk genes for Alzheimer’s through epigenetic modulation. This is being explored in neurons, glia, and animal models of neurodegeneration.
The project will involve the growth of human neural stem cell cultures and microglia cultures and treatment to elevate or decrease copper levels in cells. The effect of this on neuronal, astrocyte and microglial epigenetics will be assessed by examination of histone acetylation patterns. The effects on LOAD gene expression will be determined by qRT-PCR. The project will additionally explore copper regulation of these genes in animal models that have natural excess or deficiency of copper in the brain. The project involves cell culture, PCR, western blot, ELISA, microscopy, and additional assays.
- PhD project but may also be considered for an Honours project.