Evidence that pathological Tau functions through inhibition of lysine-specific demethylase 1A in tauopathy model mice Open Access

Moudgal, Rohitha Ananth (2016)

Permanent URL: https://etd.library.emory.edu/concern/etds/1g05fb905?locale=en
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Abstract

The pathological aggregation of Tau protein is a known hallmark of Alzheimer's disease (AD) and is sufficient to recapitulate aspects of AD in transgenic model mice. However, the processes downstream of pathological tau have not been adequately identified. Here, we provide preliminary evidence that pathological Tau functions through lysine-specific demethylase 1A (LSD1) in a mouse model of AD. LSD1 normally represses inappropriate transcription of target genes by demethylating histone H3 lysine 4, and an earlier experiment showed that LSD1 is continuously required in adult neurons for survival. Genetic reduction of LSD1 in transgenic mice expressing mutant P301S Tau accelerates aspects of the mutant Tau phenotype, such as neurodegeneration and survival, without accelerating the spread of pathological Tau. These results suggest that the inhibition of LSD1 function may be downstream of pathological Tau. Therefore, it may be possible to target the LSD1 pathway to slow the progression of AD.

Table of Contents

Introduction ........................................................................................................................... 1

Results ................................................................................................................................... 7

LSD1 Inappropriately Colocalizes with Aggregated Tau in Aged P301S Transgenic Mice...........7

Genetic Reduction of LSD1 in P301S Tg Mice Decreases Lifespan..............................................7

Genetic Reduction of Lsd1 Exacerbated Brain Atrophy in a Single TgP301S Mouse .....................8

P301S Tg Mouse Heterozygous for Lsd1 Lost Dendritic Projections ..........................................9

Genetic reduction of LSD1 in a TgP301S mouse did not accelerate spread of pathological Tau...9

P301S Tg Mouse Heterozygous for Lsd1 Exhibits Abnormal LSD1 Localization........................11

Genetic Reduction of LSD1 results in Decreased Lifespan of TgP301S Mice Despite Attenuation of tauopathy Phenotype...........................................................................................................12

Discussion .............................................................................................................................13

Experimental Procedures.......................................................................................................17

Figures and Supplemental Figures .........................................................................................23

References ............................................................................................................................36

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