Investigating LSD1 interaction with tau aggregates by examining LSD1 in rare tauopathy cases Open Access
Kang, Semin (Spring 2022)
Abstract
Alzheimer’s disease (AD), which affects over 10 million people across the world per year, is a secondary tauopathy characterized by abnormal aggregation of β-amyloid plaques and neurofibrillary tangles of hyperphosphorylated tau (NFTs). However, the mechanism underlying tau-mediated neurodegeneration is not well studied. Previously, our lab has shown that the inhibition of the lysine-specific histone demethylase, LSD1 in adult mice induces cortical and hippocampal neurodegeneration, learning and memory deficits, and transcription alternations that match human AD cases. Additionally, we have found that reduction of LSD1 in PS19 tau mice, a transgenic line that overexpresses an aggregation prone version of tau throughout the nervous system, exacerbates neurodegeneration while overexpression of LSD1 rescues hippocampal neurodegeneration. Most importantly, LSD1 colocalizes with cytoplasmic pathological tau in P301S tau mice and human AD cases. Based on this, we hypothesize that after translation, LSD1 interacts with pathological tau in the cytoplasm. This process will prevent LSD1 from entering the nucleus and cause neurodegeneration. AD and other types of rare tauopathy cases, such as Corticobasal Degeneration (CBD), Progressive supranuclear palsy (PSP), Pick’s Disease, and Frontotemporal dementia with parkinsonism-17 cases have varying tau pathology. This provides an unique opportunity to interrogate the specificity of LSD1’s interaction with pathological tau. To examine this specificity, we perform LSD1 immunohistochemistry in tauopathy and age matched non-demented cases. We recapitulated the pathological tau tangles in AD cases. In addition, we observed some abnormally shaped LSD1 staining in rare tauopathies cases and noted that the LSD1 may be primarily interacting with 4R isoforms of tau rather than the 3R isoform, specifically associating with the tufted astrocytes in the PSP pathology. We believe that this finding of potential LSD1 interaction can provide further insight into how LSD1 can provide a linkage to addressing the neurodegenerative diseases of various tauopathies.
Table of Contents
Chapter I - Introduction............................................................................................... 1
A. Figures................................................................................................................... 7
2. Chapter II - Methodology.......................................................................................... 9
A. LSD1/pathological Tau AT8 Immunohistochemistry......................................... 10
B. Information about cases....................................................................................... 11
3. Chapter III - Results................................................................................................. 12
A. AD....................................................................................................................... 14
B. AD-TDP43........................................................................................................... 15
C. PSP....................................................................................................................... 16
D. Pick’s Disease...................................................................................................... 17
E. CBD..................................................................................................................... 19
4. Chapter IV – Discussion and Future Directions...................................................... 20
5. Chapter V - References............................................................................................ 27
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