Endosomal dysfunction is one of the earliest pathological manifestations of Alzheimer?s disease (AD) leading to transport defects and increased accumulation of intracellular A?1-42. The central role of the endosomal system in AD is supported by genetic and functional studies, but it remains only partially understood how endosomal dysfunction can be triggered even in the absence of genetic lesions. We identified a transcription factor complex that is specifically induced in primary neurons treated with oligomeric Abeta1-42 as well as in neurons in Alzheimer?s disease but not age-matched control brains. We identified putative target genes of this complex by studying its promoter binding in human AD brain and by analyzing expression data from several hundred late onset AD and control cases. The functional analysis of these gene targets revealed that many of their protein products function in vesicle transport, especially at the level of the early endosome. Here we propose that the newly identified transcription factor complex is a master regulator of components of the retromer, a multiprotein complex that mediates the sorting and transport of proteins out of early endosomes. We propose to study the relationship of the upregulation of the transcription factor complex and retromer deregulation in postmortem brain samples from AD patients and non-demented controls, and in a transgenic mouse model for AD. We will determine the sufficiency of the transcription factor complex to deregulate the expression of retromer components and to cause endosomal trafficking defects. We will create a neuron- specific knockout mouse for one component of the AD-specific transcription factor complex and cross these animals with AD-model mice, to determine whether this transcription factor is required for the development of endosomal trafficking defects and neuronal cell loss in these animals. Together, the results from this project will characterize the importance of a disease-specific transcription factor complex for a central AD pathology. The knowledge gain in this research might provide a scientific rationale for novel strategies to develop disease-modifying therapies for AD.
Alzheimer?s disease is a neurodegenerative disorder for which there is currently no cure. We have found a transcription factor complex that is specifically upregulated in AD and that deregulates the expression of protein critical for intracellular vesicle transport and sorting. We propose to study the functional consequences of this complex; we expect that the results from our research will have relevance for the understanding of the disease progression in AD.
