Project Summary
Alzheimer's disease (AD) is the most common cause of elderly dementia and currently there are no effective
treatments. Selective neuronal vulnerability, appearance and accumulation of amyloid-ß (Aß) plaques, altered
circuitry function, synaptic loss and degeneration are hallmarks of AD. Microglia and astrocytes, two major
subtypes of glial cells, contribute to these neuropathological changes. However, the precise mechanisms
controlling these processes remain elusive. One of the reasons may be that we still lack the information about
the cell type-specific alterations and how they contribute to the onset and progression of AD. Here, we
postulate that by revealing detailed changes in functional networks of genes in microglia and astrocytes, and
how those processes intersect, we may be able to determine their contribution to neuropathological changes in
AD. We will utilize Translational Ribosomal Affinity Purification combined with novel bioinformatics tools to
construct functional network models of glial-specific functions and integrate these with AD quantitative genetic
data. Using this framework, we will detect glial-specific genes most likely associated with AD pathology in an
unbiased data-driven way and further investigate the functional network modules between astrocytes and
microglia. Relevant candidate genes from this analysis will be examined in vitro for their role in AD progression,
and emphasis will be given to cytokine-cytokine receptor pathways, especially interleukin 1 and colony
stimulating factor 1 hubs. We will utilize primary cell cultures and co-cultures with astrocytes and microglia
isolated from healthy and 5xFAD mice. Furthermore, we will investigate only genes that are relevant to the
human pathology. To achieve this, we will test the appearance of AD hallmarks and/or the rescue phenotype in
the microglia and astrocytes derived from the induced pluripotent stem cells (iPSC) isolated from AD patients
and healthy controls. Finally, the most important gene candidates will be tested in vivo by gene expression
manipulation in the appropriate mice lines. We will measure: i) Aß accumulation, uptake, and degradation by
microglia and astrocytes, ii) neuronal degeneration, iii) synaptic function, including synaptic markers and
functional circuitry, iv) plaque formation, and v) cognitive function, assessed with a battery of behavioral tests.
The proposed study will reveal the molecular profile of each cell type and examine their interaction. Generated
datasets and bioinformatics tools will be shared with the public via web-based interface. These data will offer
new insights into the appearance of the AD hallmarks and elucidate the basic mechanisms of the disease.
Studying these changes, especially on the whole genome level, will engender tremendous insights into
alterations in the individual genes, as well as pathways, and may offer new approaches to studying the cause
of AD, as well as reveal novel therapy targets.