Directly Reprogrammed Neurons Express MAPT and APP Splice Variants Pertinent to Ageing and Neurodegeneration

In this study, we characterised the dynamics of theMAPT andAPP alternative splicing during a developmental time-course of porcine and murine cerebral cortices. We found age-dependent and species-specific isoform composition ofMAPT, including 3R and 4R isoforms in the porcine adult brain similar to that of the adult human brain. We converted adult and embryonic fibroblasts directly into induced neurons and found similar developmental patterns of isoform composition, notably, the 3R and 4R isoforms relevant to the pathogenesis of Alzheimer ’s disease. Also, we observed cell-type-specific isoform expression ofAPP transcripts during the conversion. The approach was further used to generate induced neurons from transgenic pigs carrying Alzheimer ’s disease-causing mutations. We show that such neurons authentically model the first crucial steps in AD pathogenesis.

http://link.springer.com/10.1007/s12035-020-02258-w

Source: Molecular Neurobiology - January 7, 2021 Category: Neurology Source Type: research