Genome wide association studies have provided evidence for a significant association between ZNF804A (zinc finger protein 804A) - specifically the intronic single nucleotide polymorphism (SNP) rs1344706 - and schizophrenia, but little is known about the function of the gene or the effects of the SNP. By studying post-mortem human brain tissue, I characterised ZNF804A immunoreactivity in adult and foetal human brain and investigated effects of diagnosis and rs1344706 genotype on ZNF804A mRNA and protein expression. Secondly, I looked in a large sample of healthy volunteers (n=922) at the effects of rs1344706 on brain structure using volumetry and voxel based morphometry (VBM). Furthermore, I recruited healthy volunteers who were either homozygous for the risk allele or homozygous for the non-risk allele (n=50). They participated in magnetoencephalography (MEG) and magnetic resonance (MR) sessions in which brain activity was measured during a working memory task, a visual processing task, and rest. Using magnetic resonance spectroscopy, also neurotransmitter levels were assessed. The experiments conducted for this thesis showed for the first time that ZNF804A immunoreactivity can be detected in both foetal and adult human brain and that it is mainly localised to layer III pyramidal cells, with a granular subcellular distribution throughout the cytoplasm. No effect of rs1344706 on mRNA and protein expression was found. In our structural MRI study, rs1344706 did not affect macroscopic brain structure as measured by volumetry and VBM, and given the large sample size, this seems a convincing negative. However, we did find that rs1344706 alters prefrontal-hippocampal connectivity, with increased connectivity being observed in risk homozygotes. Additionally, using MEG, we found an effect of ZNF804A genotype on hippocampal connectivity in the theta band (4-8Hz), with non-risk homozygotes displaying more connectivity. This finding provides a first clue as to the mechanisms that might underlie the previously observed effects of rs1344706 on prefrontal-hippocampal connectivity. Future studies will need to elucidate the actual function of the ZNF804A protein, in order to bridge the gap between the molecular and neuroimaging findings described in this thesis.

Alzheimer’s Disease, also called AD, is a horrible, degenerative brain disease that more than 35 million people over the world have. Today, there is no cure for this disease, only treatments that are temporarily relieving the symptoms. The two proteins that is thought to be the main cause of AD is amyloid β (Aβ) and tau. Previously, people have tried studying Aβ in vivo using green fluorescent protein fusion together with Aβ. However, this is difficult since the aggregation of Aβ will lead to loss of fluorescence. This study aimed to crystallize the fusion protein mNG-A β1-42 and to investigate its properties as a molecular fluorescent Aβ-amyloid specific probe. Dynamic light scattering (DLS) was used to confirm that the majority of the protein was not in the form of soluble aggregates. The DLS experiments were followed by several rounds of crystallization trials. Initial screening and the subsequent narrowing down of potential conditions where mNG-Aβ1-42 could form crystals. Several staining experiments were conducted as well, including staining brain tissue from mouse with both Swedish and Arctic mutation, from human patients with sporadic AD and from human patients with AD with the Arctic mutation. The DLS experiments showed that the protein used in the crystallization experiments mostly consisted of molecular particles of the same radius. However, there was clear evidence of some larger species present that could have been a potential problem for crystallization. Crystallization experiments suggested that PEG 8000 was the most promising precipitant amongst other conditions identified for crystallization of mNG-Aβ1-42. However, the study was ultimately unsuccessful in developing crystals of sufficient high quality for diffraction studies to commence. The staining experiments demonstrated that mNG-Aβ1-42 could bind both by itself and with another amyloid probe, Congo red, and with antibodies in brain tissue from mouse with both Swedish and Arctic mutation, from human patients with sporadic AD and from human patients with AD with the Arctic mutation. In conclusion, several characteristics of mNG-Aβ1-42 were revealed in this study.