Theses Doctoral

The role of microRNA-219 in Alzheimer’s Disease-related tau proteostasis and pathology

Cho, Joshua

Alzheimer’s Disease (AD) is a chronic neurodegenerative disease characterized by cognitive impairment, progressive memory loss, dementia, and behavioral disturbances that are associated with particular histological and molecular features, principally: neuritic plaques formed from deposits of amyloid beta protein (Aꞵ) and neurofibrillary tangles composed of accumulations of tau protein. Other factors such as lipid metabolism, neuroinflammation, protein homeostasis, cell death, and synaptic dysfunction also contribute to AD pathology. In addition to these factors, numerous studies have underlined the significant impact that miRNAs and the dysregulation of miRNAs can have in mediating multiple components of AD and tau pathology. In this thesis, we focused on the role of a highly-conserved, brain-enriched miRNA, miR-219, that our laboratory had previously found to be significantly downregulated in postmortem AD brain samples and could regulate the protein levels of tau and kinases that phosphorylate tau (GSK3ꞵ, CaMKIIɣ, and TTBK1) both in vitro and in vivo in D. melanogaster.

Furthermore, we found that miR-219 could also mediate tau pathology, as evidenced by phosphorylated tau, in vitro and in D. melanogaster in vivo. This evidence led us to study whether these previously validated actions of miR-219 would be recapitulated in vivo in a mouse model of human tau pathology, htau, and illuminate whether or not miR-219 could be a potential therapeutic target or primary contributor for human AD and tau pathology. In order to do this, we overexpressed the levels of miR-219 in aged htau mice with tau pathology but unfortunately found no neuroprotective effect. Possibly due to the variability in behavioral results in this mouse model, we next provided an updated behavioral characterization of aged htau mice in a battery of useful memory tests often used in AD research.

Lastly, we inhibited the levels of miR-219 in htau mice at an age before severe tau pathology occurs in order to see if miR-219 dysregulation could exacerbate tau pathology and associated cognitive impairment. We found that miR-219 inhibition led to severe deficits in short-term spatial memory in Y-Maze Novel Arm and long-term spatial and reference memory in Morris Water Maze. Furthermore, we performed biochemical analyses on the brains of these mice and found that miR-219 inhibition led to significantly increased protein levels of CaMKII, which has been extensively implicated in AD and could underlie the memory deficits seen in these mice. Upon immunofluorescence staining and analysis of brain sections taken from these mice, we found significantly higher levels of phosphorylated tau in cells transfected with our lentiviral miR-219 inhibitor in htau-Inh mice, indicating that inhibition of miR-219 leads to increased phosphorylated tau.

Due to the design of our lentiviral vector, it is also possible that we inhibited miR-219 in other cell types in the brain (e.g., oligodendrocytes, microglia, astrocytes) whose function have been shown to be regulated by miR-219, and thus opens up many interesting future questions and research directions to fully analyze the effect that miR-219 inhibition may play in these cells and their contribution to cognitive impairment and tau pathology. We believe that our results demonstrate a critical role for miR-219 as an important contributor to both cognitive impairment and AD-related pathology, presumably through its regulation of CaMKIIɣ and the subsequent increase in phosphorylated tau.


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More About This Work

Academic Units
Cellular, Molecular and Biomedical Studies
Thesis Advisors
Perez, Ismael Santa-Maria
Hussaini, Syed A.
Ph.D., Columbia University
Published Here
October 12, 2022