Abstract
The pathology of Alzheimer's disease involves a long preclinical period, where the characteristic clinical symptoms of the changes in the brain are undetectable. During the preclinical period, homeostatic mechanisms may help prevent widespread cell death. Evidence has pointed towards selective cell death of diseased neurons playing a potentially protective role. As the disease progresses, dysregulation of signaling pathways that govern cell death contributes to neurodegeneration. Aberrant activation of the c-Jun N-terminal kinase pathway has been established in human and animal models of Alzheimer's disease caused by amyloid-beta 42- or tau-mediated neurodegeneration. Clonal mosaic studies in Drosophila that examine amyloid-beta 42 in a subset of neurons suggest complex interplay between amyloid-beta 42-expressing and wild-type cells. This review examines the role of c-Jun N-terminal kinase signaling in the context of cell competition and short-range signaling interactions between amyloid-beta 42-expressing and wild-type neurons. Cell competition is a conserved phenomenon regulating tissue integrity by assessing the fitness of cells relative to their neighbors and eliminating suboptimal cells. Somatic clones of amyloid-beta 42 that juxtapose genetically distinct neuronal cell populations show promise for studying neurodegeneration. Generating genetic mosaics with labeled clones of amyloid-beta 42- or tau-expressing and wild-type neurons will allow us to understand how short-range signaling alterations trigger cell death in neurons and thereby contribute to the progression of Alzheimer's disease. These approaches have the potential to uncover biomarkers for early Alzheimer's disease detection and new therapeutic targets for intervention.
