Targeted Downregulation of Ameliorates Tau-engendered Defects in .

BACKGROUND

Tauopathies, a class of neurodegenerative diseases that includes Alzheimer's disease (AD), are characterized by the deposition of neurofibrillary tangles composed of hyperphosphorylated tau protein in the human brain. As abnormal alterations in histone acetylation and methylation show a cause and effect relationship with AD, we investigated the role of several Jumonji domain-containing histone demethylase () genes, which have yet to be studied in AD pathology.

METHODS

To examine alterations of several genes in AD pathology, we performed bioinformatics analyses of gene expression profiles in brain tissue samples from deceased AD patients. Furthermore, to investigate the possible relationship between alterations in gene expression profiles and AD pathology in vivo, we examined whether tissue-specific downregulation of homologs () can affect tau-induced neurotoxicity using transgenic flies containing the UAS-Gal4 binary system.

RESULTS

The expression levels of , , and were significantly higher in postmortem brain tissue from patients with AD than from non-demented controls, whereas mRNA levels were downregulated in the brains of patients with AD. Using transgenic flies, we revealed that knockdown of (homolog to human ), (homolog to human ), (homolog to human ), or (homolog to human ) genes in the eye ameliorated the tau-engendered defects, resulting in less severe phenotypes. However, kdm4a knockdown in the central nervous system uniquely ameliorated tau-induced locomotion defects by restoring heterochromatin.

CONCLUSION

Our results suggest that downregulation of expression may be a potential therapeutic target in AD.