Cell-Cell Interactions In Alzheimer's disease and related dementias

University Of Dayton, Dayton OH

Investigators

Linked publications, trials & patents

Abstract

Alzheimer’s disease (hereafter, AD), a progressive neurodegenerative disorder, is fatal with no effective cure to date. AD manifests as gradual decline in cognitive functions of learning and memory due to selective atrophy of the hippocampus and frontal cerebral cortex in the brain. The neurodegeneration associated with AD also coincides with accumulation of amyloid-beta 42 (Aß42) plaques. The accumulation of Aβ42 plaques and NFTs in AD triggers progressive neurodegeneration across brain regions. It is not clear how cellular changes contribute to the progression from an initial asymptomatic period into a phase of stark cognitive decline. The molecular genetic mechanisms underlying the Aβ42 mediated neurodegeneration are not fully understood. Many strategies including model organisms have been devised. Drosophila melanogaster, fruit fly, with a large array of genetic tools, and similar genetic makeup to humans is an excellent model for human diseases including AD. Drosophila can be used for high throughput genome wide- and for therapeutic compound screens. We have established a transgenic fly model where we misexpress high levels of human Aß42 polypeptides in the retinal neurons of the eye, which exhibits AD like neuropathology of progressive neuronal death. This stable transgenic line exhibits Aß42 mediated cell death in nearly 100% flies at 29oC. Our goal is to employ our Drosophila eye model to identify (a) downstream target genes and (b) reporters/ sensors to detect AD, and (c) look for complex interaction between Aß42-producing and wild-type neurons during Alzheimer’s neuropathology. We identified the highly conserved growth regulatory Wingless (Wg)/Wnt signaling pathway as the dominant modifier of Aß42-mediated neurodegeneration. The first aim is to determine the involvement of Wg signaling in Aβ42-mediated neurodegeneration. Wg signaling has been studied in cell survival and differentiation, and not in neurodegeneration. We will test if modulation of the Wg signaling pathway can modulate Aβ42-mediated neurodegeneration. We will test if the reporters/sensors of the Wg pathway can be used to detect Aß42-mediated neurodegeneration. In the second aim, we will determine if Wg pathway activation triggers neurodegeneration in wild-type cells or in Aβ42-expressing cells. We will use our two clone systems to determine if there is any cross-talk between the wild-type neurons and Aß42 producing neurons. Our hypothesis is that aberrant Wg signaling might trigger cell death in wild-type neurons. These proposed studies aim to provide a useful blueprint to study cross-talk between cell populations in neurodegenerative disease. This may potentially identify new biomarkers that can be differentially regulated between Aβ42-expressing and WT neurons. Better understanding of the local context of cell death in progressive neurodegenerative disease is a vital next step in developing new interventions to slow or halt disease progression.