Neurodegenerative Diseases

Tau is a multifunctional microtubule-associated protein that is highly abundant in the brain and predominantly expressed in neurons where it has a role in microtubule assembly and stability, axonal transport and neurite outgrowth. Toxic Tau aggregates are part of the neuropathology of several neurodegenerative diseases collectively known as ‘tauopathies’ including Alzheimer’s disease. 

In order to elucidate the functional intricacy of Tau and develop effective Tau-based therapies, there is an urgent need for the better understanding of the complex regional and cellular regulation of alternative Tau transcripts in development, normal versus diseased brains and various mouse models used to study disease pathologies.

In our recent study, we used the BaseScope™ ISH assay to visualize the alternative splicing of exon 10 and quantify the neuroanatomic expression of 3R (exon 10 exclusion) and 4R (exon 10 inclusion) Tau splice variants at the single cell level within the morphological tissue context during mouse brain development (C57Bl/6J mice) in postnatal ages P1, P10, P30, and P56 (Figure 1).


FIGURE 1. Schematic of BaseScope™ probe design for detection of 3R and 4R Tau splice variants.

Quantification of the 3R:4R Tau ratio showed that both isoforms are developmentally regulated and revealed a clear opposite dynamic in their expression over the course of development in the investigated brain areas including cortex and hippocampus. 


FIGURE 2. Quantitative isoform expression analysis to generate 3R:4R Tau ratio over development (HALO™ Indica Labs).

In addition, we found distinct subregional and layer-specific differences in the expression patterns of both isoforms. 


FIGURE 3. Layer-specific expression patterns for 3R (A, C) and 4R (B, D) Tau isoforms exemplified in hippocampus (Dentate Gyrus) and cerebellum at developmental age P10.

Beyond development, the probe design in this study is applicable to various cell-based and animal models to elucidate the role of each splice variant in various neuronal tauopathies in the search for effective Tau-based therapies. 

 

Neuroscience Gene List

(click on gene name to access corresponding RNAscope® probes)

 

 

 

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