Double-stranded RNA in neuronal cell death in Alzheimer's and related neurodegenerative diseases

Project Summary Alzheimer's disease (AD) and related neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are characterized by neuroinflammation and neuronal cell death. Also associated with these diseases is an abnormal deposition of the TDP-43 protein. This protein has multiple roles in RNA metabolism, and we have previously demonstrated that one of its functions is to limit the accumulation of double-stranded RNA (dsRNA). dsRNA rarely accumulates in normal cells (particularly in the cytoplasm), but commonly occurs during viral infection. Thus, abnormal dsRNA is recognized by cells as a sign of infection, leading to the induction of an antiviral innate immune response and the induction of cell death pathways. The central hypothesis we will test in this proposal is that in AD and ALS/FTD the accumulation of dsRNA induces inappropriate activation of antiviral responses that contribute to the observed neuropathology. Our goals are to determine: 1) the underlying molecular mechanisms that lead to dsRNA accumulation, and 2) how dsRNA accumulation leads to glial and neuronal dysfunction. Characterization of pathways that lie both upstream and downstream of dsRNA accumulation in the context of AD, ALS/FTD, and other neurodegenerative diseases has the potential to generate novel therapeutic targets for these currently untreatable pathologies. Our preliminary studies demonstrate that dsRNA accumulates in the hippocampus of Alzheimer's patients and the motor cortex of ALS patients. We will immunopurify and sequence this dsRNA from human brain to determine its origins. Transgenic mouse models with conditional depletion of TDP-43 will be characterized to define the temporal relationships between TDP-43 loss, dsRNA accumulation, gliosis, and neuronal cell death. Infection of human iPSC-derived neural cultures with engineered lentivirus and infection of mouse models with engineered adenovirus will be used to artificially generate dsRNA to investigate the pathways by which dsRNA leads to disease-relevant neuropathology.