AbstractsBiology & Animal Science

Investigating the potential of stem cell based therapy in murine models of Alzheimer's disease

by Durgesh Tiwari

Institution: Monash University
Department: Drug Discovery Biology
Year: 2015
Keywords: Alzheimer's disease; Stem cells; Mouse models; Watermaze; Cholinergic neuron
Record ID: 1059000
Full text PDF: http://arrow.monash.edu.au/hdl/1959.1/1146437


Forebrain cholinergic neuronal loss is strongly correlated with the memory impairment of Alzheimer’s disease (AD). Current therapeutic options provide short term symptomatic relief and only minimally affect disease progression. Thus, any potential stem cell therapy with the ability to reverse the cell loss and halt the disease progression would be a valuable therapeutic option. The overarching aim of this thesis was to investigate the ability of transplanted neural progenitor cells to restore cognitive function in mouse models of Alzheimer’s disease. A dual reporter system was employed to identify specific populations of mouse embryonic stem (mES) cells, with mcherry (a red florescent protein) targeted to the ROSA26 (thumpd 3) promoter and β lactamase-T2A-β- galactosidase targeted to the Lhx8 promoter, designed to enrich cultured cells for cholinergic progenitors. Two different mouse models of AD, the acquired immunotoxin based model and the genetic triple transgenic model of AD (3xTg-AD), were validated using two behavioural paradigms measuring hippocampal (spatial memory) and cortical (declarative memory) function via a modified water maze and novel object recognition paradigm. Immunotoxin treated mice were later implanted with neural precursor cells and their cognitive function was then evaluated post-transplantation. In the first chapter (chapter3), the immunotoxin mouse model was investigated. The model uses mu-p75-saporin, a ribosomal inactivating toxin directed against the p75 nerve growth factor receptor, to cause the degeneration of forebrain cholinergic neurons as observed in AD. Intracerebroventricular injections of mu-p75- saporin caused cholinergic cell loss which was behaviourally correlated with spatial memory deficits in the water maze but intact recognition memory in novel object paradigm. Post mortem analyses revealed a reduction in the number of choline acetyltransferase (ChAT) positive cells in the principle regions providing cholinergic innervations to the hippocampus. Together, these data suggests that mu- p75-saporin treated mice represent a suitable model for the investigation of spatial memory deficits in future stem cell experiments. In chapter four, the 3xTg-AD mouse model was investigated. 3xTg-AD mice express three human transgenes, the amyloid precursor protein (APPswe), presenilin 1 (PS1M146V), and tau (tauP301L), and exhibit age related insoluble Aβ and neurofibrillary tangle (NFT) pathologies, as observed in human AD patients. Cognitive function in 3xTg-AD mice was assessed at 12 - 14 months and 16 - 18 months of age, again using the same modified water maze and novel object recognition paradigms. Deficits in recognition memory were observed in both male and female 3xTg-AD mice at both age points. However, in the water maze both WT and 3xTg-AD mice exhibited spatial memory deficits, making the data inconclusive. Tau based tangle pathology was detected in the hippocampus, amygdala and cortex of transgenic mice; however Aβ pathology was completely absent in the aforementioned regions.…