TDP-43 deltaNLS Transgenic ALS Mouse Model

Table of Contents

Abstract

Presentation

01. Introduction 02. Regional Volumes Analysis Methods 03. Cortical Thickness Analysis Methods 04. TDP-43 Model 05. TDP-43 Model MR Images 06. TDP-43 Model MRI Analysis 07. Alpha-Synuclein Model 08. Synuclein Model MR Images 09. Synuclein Model MRI Analysis 10. Summary

We use both the original rNLS8 (or ΔNLS) mouse model (in-licensed by Biospective), as well as a less aggressive version implemented by Biospective:

Original mouse model ("Off Dox"): rapid progressing (weeks)
Biospective mouse model ("Low Dox"): slower progressing (months)

Key features of this mouse model include:

Nuclear-to-cytoplasmic TDP-43 mislocalization
Phosphorylated TDP-43 aggregates
Neurodegeneration & muscle atrophy
Brain, spinal cord, and neuromuscular junction pathology
Motor deficits

Briefly, mice are on a doxycycline (Dox) diet during breeding and the initial aging period (5 to 12 weeks-of-age). In the standard model, the mice are changed from a Dox diet to a standard diet ("Off Dox" model) to allow for human TDP-43 expression. In the Biospective-modified model, the mice are switched from the Dox diet to a standard diet for a short period and then maintained on a lower Dox dose diet ("Low Dox" model).

A unique feature of this model is the ability to achieve functional and pathologic recovery by placing the mice back on a doxycycline diet to halt TDP-43 expression.

https://opt003stagmediafiles.blob.core.windows.net/image/79a7fb598200416cb8157a05d93728a5

https://opt003stagmediafiles.blob.core.windows.net/image/831db19350d54d60bd78051a4d5e67d8

Low and high magnification views of human pan-TDP-43 pathology in the brain. Note the strong staining of cytoplasmic aggregates and lack of nuclear staining.

Please note that we provide a link to our ALS and other CNS disease models on the last page of this presentation.

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We have applied MRI brain atrophy analysis to the TDP-43 mouse model of ALS that we routinely use for preclinical therapeutic efficacy studies.

The model works by maintaining mice on a doxycycline (Dox) diet during breeding and the initial aging period of typically 8 to 12 weeks-of-age. In the standard model, the mice are changed from a Dox diet to a standard diet to allow for human TDP-43 expression. We call that the "Dox Off" model. In our Biospective-modified model, the mice are switched from the Dox diet to a standard diet for a short period and then maintained on a lower Dox dose diet. We call that the "Low Dox" model.

A unique feature of this model is the ability to achieve functional and pathologic recovery by placing the mice back on a Dox diet to halt TDP-43 expression.

In this presentation, we show data from both the "Off Dox" and "Low Dox" models at different time points after the removal of doxycycline.