Alzheimer's disease is a progressive disease of the brain that leads to loss of cognitive function and is the most common form of dementia. More than 5.5 million Americans over the age of 65 are affected by Alzheimer's disease. Amyloid plaques and neurofibrillary/tau tangles are thought to be the primary characteristics of Alzheimer's disease.

RNA splicing removes introns and generates mature mRNA transcripts and is key for regulation of gene expression in cells. RNA splicing is one of the important ways by which organs generate different cell types, each of which perform specialized functions and is especially critical to generate cellular diversity and complexity in the human brain. Minor perturbations in the assembly and/or function of the spliceosome are predicted to render brain cells vulnerable to degeneration and premature death, particularly in aging individuals.

Data from the study reveals a novel mechanistic link between alterations in RNA splicing and tau-mediated neurodegeneration in Alzheimer's disease. The team investigated if aggregates of tau protein within neurons, a key marker of the disease, interfere with RNA splicing.

"Alterations in RNA splicing are known to be involved in the development of certain neurodegenerative conditions, such as spinal muscular atrophy and amyotrophic lateral sclerosis. However, until now, their role in Alzheimer's disease was not studied in great detail," said Joshua Shulman, associate professor of neurology, neuroscience and molecular and human genetics at Baylor.

To achieve RNA splicing, researchers used the spliceosomal complex, a multiprotein cellular machinery that coordinates the production of mature RNA molecules. Tau protein, encoded by the microtubule-associated protein tau (MAPT) gene, aggregates to form neurofibrillary tangles. Previous research indicates that components of the spliceosomal complex can co-aggregate with neurofibrillary tau tangles. In the current study, scientists tested whether spliceosome-tau interactions can cause neurodegeneration. They began by testing this hypothesis in fruit flies and then moved to human postmortem brains.

Using a panel of RNA sequencing and PCR analysis, in combination with computational analysis, the researchers were able to determine specific splicing errors that occur with low frequency in a large dataset. "Identifying and classifying specific splicing errors turned out to be fairly difficult. Current computational tools that analyze RNA sequencing datasets typically filter out any change that does not match the normal RNA splicing patterns. We had to specifically look into this 'junk material' to identify patterns of specific splicing errors," said Zhandong Liu, associate professor of pediatrics-neurology at Baylor. Researchers modified a novel computational tool, CrypSplice to perform in-depth analysis of splicing errors, which uncovered a link between tau tangles and an increase in a particular type of splicing errors.

The researchers showed that:

• Many spliceosome components are physically associated with Tau in human brains with Alzheimer's disease pathology, and in Drosophila, genetic manipulation of these factors enhances Tau neurotoxicity
• Transgenic expression of human Tau causes a reduction of multiple spliceosome components, and loss of function of the core spliceosome protein, SmB, which induces progressive neuronal dysfunction
• Tau induces splicing errors in Drosophila similar to genetic disruption of the spliceosome, and confirm that increase cryptic splicing load in human brain matches the tau pathology observed in Drosophila

"This is the first study to demonstrate the role of tau aggregates in disrupting the cellular localization and function of spliceosomal complex components that result in global splicing errors and cause progressive loss of neurons," Shulman said. "Our findings present an exciting new possibility of using RNA splicing as a potential molecular target for Alzheimer's disease and other tau-mediated neurodegenerative conditions."

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