Dementias are among the most common neurological disorders and Alzheimer’s disease (AD) is the most common cause of dementia worldwide. of FTDs are collectively known as tauopathies due to the abundant accumulation of pathological tau inclusions in the brain. The precise role tau plays in disease pathogenesis remains an area of strong research focus. A critical component to effectively study any human disease is the availability of models that recapitulate key features of the disease. Accordingly a number of animal models are currently being pursued to fill the current gaps in our knowledge of the causes of dementias and to develop effective therapeutics. Recent developments in gene therapy-based approaches particularly in recombinant adeno-associated viruses (rAAVs) have provided new tools to study AD and other related neurodegenerative disorders. Additionally gene therapy approaches have emerged as an intriguing possibility for treating these diseases in humans. This chapter explores the current state of rAAV models of AD and other dementias discuss recent efforts to improve these models and describe current and future possibilities in the use of rAAVs and other viruses in treatments of disease. Chapters 1 and 10 for more details on rAAV biology and transduction mechanisms). Importantly the transduction specificity (i.e. cell-type selectivity) ability to inject into specific brain regions and at specific times in lifespan long-term gene expression and lack of eliciting a strong immunogenic response make rAAVs ideal for modeling neurodegenerative diseases. In addition to their potential in basic research they also show promise as gene transfer therapeutics for neurodegenerative diseases in the CNS. 4 Advantages of Viral Vector Systems Viral delivery systems hold a number of advantageous characteristics that are difficult to achieve with other approaches. Viral vector systems provide exquisite control over the temporal expression of the gene of interest. AD and other tauopathies are all adult-onset and aging remains the primary risk factor of developing AD. Thus studies that introduce the production of disease-related genes of interest should incorporate this important Clozapine variable by expressing the genes in adult or elderly animals. Delivery of viral Clozapine vectors is completely under the control of the researcher which easily facilitates studies where animals are transduced at any point in the lifespan. For example injection of rAAV2/5-GFP and rAAV2/5-human wild-type tau (2N4R) into the HP of young adult (6 months) and old aged (20 months) Fischer 344 rats results in efficient neuronal transduction and similar levels of protein expression after 1 month (Fig. 1). Our group recently found that rAAV2/5-GFP transduction in the SN is reduced in aged animals compared to young animals [82] but other studies have shown that rAAV2/9-tau and -GFP transduction is unaffected in the SN [83 84 The differences in transduction efficiency with age may reflect the use of different rAAV serotypes. These studies suggest that transduction efficiency in aging animals differs in specific brain regions and with different rAAV serotypes. Virally Clozapine transduced cells maintain expression of the protein without the addition of other molecules for the remainder of the lifespan. Much like inducible transgenic lines rAAV-mediated expression can be further regulated if tetracycline regulatory elements are incorporated into the Rabbit Polyclonal to MYOM1. rAAV systems [85]. Fig. 1 rAAV2/5 efficiently transduces neurons and produces equal protein expression in the young and aged rat hippocampus (HP). (a–d) Young adult (a and c 6 months = 3) and old aged (b and d 20 months = 3) Fischer 344 rats were injected with … In addition to great temporal control viral vectors provide control over the spatial expression of the transduced genes. AD and other tauopathies are characterized by the degeneration and pathological accumulation of proteins in specific brain regions. For example the EC and HP are primary affected areas in AD while other tauopathies involve degeneration in the frontal and Clozapine temporal cortices as well as the basal ganglia brainstem and cerebellum. Viral vectors allow researchers to stereotaxically inject viruses in relatively discrete brain regions of interest. For example direct injection of rAAVs into the rat HP or EC results in efficient transduction of neurons (Fig. 2). Furthermore unilateral injections allow the contralateral half of the brain to serve as a control within the same animal but the contralateral projections of a specific region must be considered. Another.