Studies in cell culture and in animals suggest that neuregulin 1 (NRG1), a probable schizophrenia susceptibility gene, regulates the expression of the alpha7 nicotinic acetylcholine receptors (nAChRs). We hypothesized that schizophrenia-associated allelic variations within the NRG1 gene, via their effects on NRG1 isoform expression, would be associated with alterations in nAChR alpha7 receptor levels. We examined the effects of four disease-associated single-nucleotide polymorphisms (SNPs) in the 5' region of the NRG1 gene on nAChR alpha7 mRNA transcript expression in both the dorsolateral prefrontal cortex (DLPFC) and hippocampus of normal controls and patients with schizophrenia using quantitative real-time PCR. NRG1 risk alleles at SNPs SNP8NRG221132 and rs6994992 predicted significantly lower nAChR alpha7 mRNA expression in the DLPFC. Haplotypes containing the risk alleles at the above SNPs were also associated with lower expression of nAChR alpha7 in the DLPFC. The genotype effect for rs6994992 and the haplotype effect were more pronounced within the schizophrenic patient group. To determine whether receptor levels follow that of mRNA expression, we performed receptor binding and autoradiography using [(125)I] alpha-bungarotoxin in the DLPFC. Consistent with the mRNA findings, we found a decrease in binding in risk allele carriers of SNP8NRG221132 as compared with heterozygous individuals. Together, these results suggest that the molecular mechanism of the association between NRG1 risk alleles and schizophrenia may include down-regulation of nAChR alpha7 expression.

Immunization with amyloid-β (Aβ) prevents the deposition of Aβ in the brain and memory deficits in transgenic mouse models of Alzheimer’s disease (AD), opening the possibility for immunotherapy of AD in humans. Unfortunately, the first human trial of Aβ vaccination was complicated, in a small number of vaccinees, by cell-mediated meningoencephalitis. To develop an Aβ vaccine that lacks the potential to induce autoimmune encephalitis, we have generated papillomavirus-like particles (VLP) that display 1–9 aa of Aβ protein repetitively on the viral capsid surface (Aβ-VLP). This Aβ peptide was chosen because it contains a functional B cell epitope, but lacks known T cell epitopes. Rabbit and mouse vaccinations with Aβ-VLP were well tolerated and induced high-titer autoAb against Aβ, that inhibited effectively assembly of Aβ1–42 peptides into neurotoxic fibrils in vitro. Following Aβ-VLP immunizations of APP/presenilin 1 transgenic mice, a model for human AD, we observed trends for reduced Aβ deposits in the brain and increased numbers of activated microglia. Furthermore, Aβ-VLP vaccinated mice also showed increased levels of Aβ in plasma, suggesting efflux from the brain into the vascular compartment. These results indicate that the Aβ-VLP vaccine induces an effective humoral immune response to Aβ and may thus form a basis to develop a safe and efficient immunotherapy for human AD.

Previously, pA134 was identified as one of the mRNAs present in the squid giant axon. Comparative sequence analyses revealed that the pA134 gene product manifested significant similarity to the mammalian lipoprotein receptor adaptor protein also known as ARH (autosomal recessive hypercholesterolemia). ARH mRNA and protein displayed very similar pattern of expression throughout the mouse brain. Significant levels of expression were observed in cells with a predominantly neuronal profile in the cerebellum, brainstem, olfactory bulb, hippocampus, and cortex. A yeast two hybrid screen for ARH protein interactions in mouse brain identified the following binders: amyloid precursor-like protein 1, low density lipoprotein receptor-related protein (LRP) 1, LRP8, and GABA receptor-associated protein-like 1. The interactions of ARH with LRP1 and GABA receptor-associated protein-like 1 were subsequently verified by co-immunoprecipitation of the protein complexes from transfected human embryonic kidney cells. The presence of ARH mRNA in axon of primary sympathetic neurons was established by RT-PCR analyses and confirmed by in situ hybridization. Taken together, our data suggest that ARH is a multifunctional protein whose spectrum of function in the brain goes beyond the traditionally known metabolism of lipoproteins, and that ARH may be locally synthesized in the axon.