Abstract
BackgroundUnderstanding the aetiologies of neurodegenerative diseases such as Alzheimer's disease (AD), Pick's disease (PiD), Progressive Supranuclear Palsy (PSP) and Frontotemporal dementia (FTD) is often hampered by the considerable clinical and molecular overlap between these diseases and normal ageing. The development of high throughput genomic technologies such as microarrays provide a new molecular tool to gain insight in the complexity and relationships between diseases, as they provide data on the simultaneous activity of multiple genes, gene networks and cellular pathways.Methodology/Principal FindingsWe have constructed genome wide expression profiles from snap frozen post-mortem tissue from the medial temporal lobe of patients with four neurodegenerative disorders (5 AD, 5 PSP, 5 PiD and 5 FTD patients) and 5 control subjects. All patients were matched for age, gender, ApoE-ε and MAPT (tau) haplotype. From all groups a total of 790 probes were shown to be differently expressed when compared to control individuals. The results from these experiments were then used to investigate the correlations between clinical, pathological and molecular findings. From the 790 identified probes we extracted a gene set of 166 probes whose expression could discriminate between these disorders and normal ageing.Conclusions/SignificanceFrom genome wide expression profiles we extracted a gene set of 166 probes whose expression could discriminate between neurological disorders and normal ageing. This gene set can be further developed into an accurate microarray-based classification test. Furthermore, from this dataset we extracted a disease specific set of genes and identified two aging related transcription factors (FOXO1A and FOXO3A) as possible drug targets related to neurodegenerative disease.
Highlights
Neurodegenerative diseases are characterised by regional cellular changes associated with progressive loss of neurons that on careful examination of brain pathology is generally distinctive between diseases
Clustering We performed a hierarchical cluster analysis based on similarities in gene expression without pre-grouping of samples based upon clinical, pathological or genetic characteristics
Gender, age at death, ApoE-e and Microtubule Associated Protein Tau (MAPT) haplotype could not explain why gene expression in these samples was distinct from related samples, we evaluated the medical history of these samples in more detail
Summary
Neurodegenerative diseases are characterised by regional cellular changes associated with progressive loss (of function) of neurons that on careful examination of brain pathology is generally distinctive between diseases. Neurodegenerative disorders may be distinguished upon presence and absence of disease specific protein aggregates e.g. asynuclein in Parkinson, and amyloid precursor protein in Alzheimer’s disease or the microtubule associated protein tau (MAPT or tau) as observed in for example AD, FTD, PiD, PSP [4,5]. In this last group of diseases, referred to as tauopathies, patients are often distinguishable upon pathology, patients with less typical or mixed pathology are difficult to classify, demonstrating the need to understand the underlying processes behind the pathological changes. The development of high throughput genomic technologies such as microarrays provide a new molecular tool to gain insight in the complexity and relationships between diseases, as they provide data on the simultaneous activity of multiple genes, gene networks and cellular pathways
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