Date of Award

2014

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Professor Jochen H.M. Prehn

Funder/Sponsor

Science Foundation Ireland and Irish Health Research Board

Keywords

Amyotrophic Lateral Sclerosis -- therapy, AMP-Activated Protein Kinases

Abstract

Adenosine 5'-monophosphate-activated protein kinase (AMPK) is the main sensor and regulator of energy homeostasis in the body. As abnormal energy metabolism is a well documented pathological feature of Amyotrophic Lateral Sclerosis (ALS) in patients and mouse models of ALS, we investigated AMPK as a possible therapeutic target to relieve disease phenotype in ALS mice.

Firstly, we examined AMPK signalling patterns across disease progression in SOD1G93a mice, as this mouse model is the most characterised and well understood mouse model of ALS. We observed increased AMPK activation in S0D1G93A spinal cords at symptom onset (post natal day (PND) 90) which also continued later into disease progression at PND 120. As AMPK can activate autophagy we investigated autophagy protein levels also. Similarly, we found elevated autophagy activity at PND 90.

Latrepirdine has recently been identified as a small molecular activator of AMPK. Therefore, we tested the effect of Latrepirdine treatment in primary motor neuron cells and found that it elevated AMPK activation when used at a sub-nanomolar concentration (0.1 nM). Additionally, in vivo, Latrepirdine treatment increased AMPK activation in spinal cords of S0D1G93A and TDP-43A3I5T mice when used at 1 pg/kg dose.

Furthermore, previous studies targeting AMPK in pre-conditioning treatment paradigms have proved to be neuroprotective. Transient AMPK activation is associated with pro-survival effects, while pro-longed AMPK activation can lead to cell death. Flere, we trialled Latrepirdine as a possible therapeutic agent in SOD 1G93A mice (n=24 animals per group; sex- and litter-matched), and found that ‘pre-conditioning’ treatment with Latrepirdine (1 pg/kg, i.p.) from PND 70 - PND 120 improved survival (p<0.01) and delayed the onset of motor function disabilities in these mice, particularly in males.

Moreover, we characterised AMPK signalling in another mouse model of ALS, TDP-43A315T mice. We investigated AMPK as a pharmalogical target in this mouse model using Latrepirdine as a ‘pre-conditioning’ treatment (1 pg/kg, i.p.) from PND 40 - PND 80 and found that this treatment regime increased lifespan significantly (p<0.05) also.

The work from this thesis shows that ‘pre-conditioning’ treatments using Latrepirdine may provide a possible therapeutic strategy to target AMPK in ALS. Additionally, as Latrepirdine significantly increased life span in two mouse models of ALS, this pharmalogical treatment strategy may be a possible therapeutic intervention in many sub-populations of ALS cases linked to various genetic mutations of the disease.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

File Size

12.2 MB

Comments

A thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2014.

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