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. Aplysia exhibits a predictable aging process leading to senescence and death at age 12 months. Our research has 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). We recently demonstrated that Aplysia expresses a variety of genes orthologous to those implicated in AD progression, underscoring the relevance of this model. Moreover, a natural viral infection has been identified in the nervous system of Aplysia, which may be similar to viral infections of the human brain that recently have been suggested to contribute to the onset of the amyloid proteinopathies that define AD. Recent data from our laboratory also show that viral load increases with age and may affect the aging process. Here we propose a 1-year study to test the aging Aplysia model as a model of virus-induced AD and ADRD, primarily by employing new models to analyze the Aplysia nervous system transcriptome in the context of a naturally occurring viral infection that increases with age. We will also leverage the large neurons of Aplysia to perform single cell transcriptomics in a single cell model of the effects of human mutant tau protein. This approach is based on many unique advantages of the Aplysia system for these studies. We will explore development of this model through three proposed aims: (1) Transfection of buccal S cluster sensory neurons (BSC) with mutant tau mRNA combined with single cell RNA sequencing will elucidate whether these transfections mimic the transcriptional phenotype of AD. (2) We will use an age-viral load covariate statistical model to compare low vs. high viral load Aplysia sensory neuron RNA sequencing data from our current datasets to determine the effects of viral load on the aging transcriptome and as a model for virus-induced sporadic AD. (3) We will identify potential novel antimicrobial peptides (AMP) in yet to be annotated Aplysia transcripts using motif identification-based methods to identify AMP with the capacity to form protein aggregates in a manner similar to that of amyloid beta (A?) and thus serve as more informed candidates for models of A??s AMP-like activity. The proposed research provides a targeted and unique opportunity to evaluate the potential usefulness of Aplysia as a model of AD and ADRD.
|Effective start/end date||4/1/12 → 3/31/22|
- NIH Office of the Director: $94,200.00
- NIH Office of the Director: $258,875.00
- NIH Office of the Director: $509,784.00
- NIH Office of the Director: $223,674.00
- NIH Office of the Director: $511,327.00
- NIH Office of the Director: $499,787.00
- NIH Office of the Director: $6,374,341.00
- NIH Office of the Director: $522,554.00
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