Alzheimer?s Disease (AD) is a complex, chronic syndrome, likely with multiple underlying etiologies. In spite of considerable investment, most therapeutic strategies tested to date have had disappointing outcomes. This suggests the need to explore additional model systems that will allow different approaches to testing current as well as alternative hypotheses about the etiology of AD and its related dementias (ADRD). The sea hare Aplysia californica (Aplysia) is a widely used model of neuronal cell function and the cellular basis of learning and memory. Here we propose an 8 month study to rapidly assess the potential usefulness of Aplysia as a model for AD and ADRD and specifically to evaluate the role of viral infection in these pathologies. This approach is based on many unique advantages of the Aplysia system for these studies. Aplysia exhibits a predictable aging process leading to senescence and death at age 12 months. We have recently shown that Aplysia is an excellent model of aging wherein behavioral, neurophysiological, and transcriptomic analyses can be combined to understand fundamental processes in nervous system aging. Aplysia and other mollusks have been demonstrated to be evolutionarily closer to mammals than ecdysozoan models of AD (Drosophila and C. elegans). Aplysia expresses a variety of genes orthologous to those implicated in AD progression. Furthermore, Aplysia has been successfully used as an induced model of tauopathies known to occur in AD. This suggests Aplysia has potential as a model for AD research. Recently, viral infections of the human brain have been suggested to contribute to the onset of the amyloid proteinopathies that define AD. Similarly, a natural viral infection has been identified in the nervous system of Aplysia. Recent data from our laboratory suggest that viral load increases with age, and may affect the aging process. We currently have two transcriptional datasets derived from Aplysia sensory neurons that span maturity through advanced age and varying viral load. Accompanying these datasets are behavioral and morphological phenotypes of each individual. We propose to use these datasets to determine if Aplysia neurons exhibit ADRD-like transcriptional changes in age and if those changes may be driven by viral infection. The proposed research provides a targeted and unique opportunity to evaluate the potential usefulness of Aplysia as a model of AD and ADRD and test hypotheses on the role of infections and accompanying immune responses on development of these disease processes.
Developing Aplysia as a Model of Alzheimer's Disease In spite of considerable investment, most therapeutic strategies for Alzheimer?s Disease tested to date have had disappointing outcomes. We propose to use a well-established invertebrate model of neuronal cell function, the California sea hare, to develop a novel approach to test hypotheses about development of gene expression patterns associated with Alzheimer?s Disease and related dementias. This research will evaluate the hypothesis that inflammatory responses associated with viral infection may initiate or promote changes relevant to Alzheimer?s Disease and related dementias.
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