Alzheimer's tauopathy phenotype and the microRNA22-3p: implication for pathogenesis

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PROJECT SUMMARY One common pathologic hallmark of Alzheimer's disease (AD) and related tauopathies is the abundant presence of abnormal aggregates of highly phosphorylated tau protein in the brain parenchyma. Because the etiology of the vast majority of these cases (late-onset) is not known, currently there are no effective preventative measures or therapeutic approaches against them. Considering the increasing number of individuals affected by these disorders there is a sense of urgency to identify the mechanisms responsible for the onset and development of their neuroptahologic phenotype. Recently, small non-coding RNAs, also called microRNAs (miRNAs), have emerged as important post- transcriptional master regulators of several key cellular processes involved in neurodegeneration. Consistent data in the literature showed that miRNAs are dysregulated in AD and related tauopathies. However, since these studies typically assessed a single time point in the disease evolution they did not address whether the changes antecede or follow the onset of the pathology. Using an unbiased approach, in our preliminary studies we discovered an age-dependent increase in the expression levels of a specific miRNA, miRNA22-3p, in the hippocampus of a relevant mouse model of tauopathy at an early stage of its phenotype. Importantly, we confirmed this observation also in post-mortem human tauopathy brain tissues when compared with age-matched healthy controls. Additional studies revealed that this miRNA directly modulates pathologic tau accumulation. The hierarchical hypothesis of this research program is that miRNA22- 3p directly contributes to the tauopathy pathogenesis through regulation of specific targets involved in tau metabolic pathways, and that the modulation of its level represents a new therapeutic approach for the treatment of these diseases. To test our hypothesis, we will over-express miRNA22-3p in a relevant tauopathy mouse model (Specific Aim 1) and down-regulate miRNA22-3p expression levels in the same model (Specific Aim 2). In order to establish its cellular source and contribution to the tau phenotype, we will generate tauopathy mouse models with cell- specific miRNA22-3p deficiency (Specific Aim 3). In all these models we will assess the effects and mechanisms of manipulating this specific miRNA level on tau neuropathologic phenotype and cognitive functions. Overall the long-term goal of our research proposal is to establish the functional role that miRNA22-3p plays in the pathophysiology of AD and related tauopathies, and ultimately by identifying its biological targets to develop novel and viable therapeutic tools and strategies against these devastating diseases.