AbstractAlzheimer’s disease (AD) is the most prevalent form of dementia. It is often
characterized by amyloid-β (Aβ) accumulation and aggregation, and neurofibrillary tau tangles. Many different mechanisms are hypothesized to contribute to the disease process, from a reduction in Aβ clearance, electrical imbalances leading to excitotoxicity, widespread inflammation, genetic factors, to poor nutrition and exercise.
The research presented in this thesis led to a new method of in vivo apolipoprotein E measurement using microdialysis to assess dynamic changes in response to therapeutic methods in real-time. The work presented here also establishes new methods for Aβ clearance, neuronal protection, and restoration of cognitive function in both animal and human models. Receptor-mediated endocytosis by the low-density lipoprotein receptor-related protein 1 is important in neuronal clearance of Aβ. When disrupted in conditional knock-out cell culture and murine models, Aβ plaque deposition and insoluble Aβ levels increase. Aβ can also be taken up and degraded by astrocytes. Increasing the activation of transcription factor EB stimulates the biogenesis of lysosomes and increases cellular uptake pathways that promote the uptake and degradation of Aβ by astrocytes. Our research also showed that neurons can be protected from aberrant electrical activity that is often found with AD. By constructing antisense oligonucleotides specific to endogenous murine tau, we were able to protect against hyperexcitability in chemically-induced seizures. Further, by reducing transcription of the amyloid precursor protein, which is thought to be overexpressed in AD, abnormal EEG activity was reduced without changing Aβ plaque load. A similar transgenic reduction in APP also restored cognitive function in mice by decreasing soluble Aβ while leaving plaque loads unchanged. These and other findings show that AD has multiple underlying mechanisms that contribute to AD disease state and progression. Taking the multifactorial nature of the disease into account, further research led to the creation of a combination therapy approach informed by precision medicine software that enabled the creation of a personalized therapeutic approach to AD. This software was then further expanded to track and enable improved prescription methods to prevent interactions and cognitive burden related to polypharmacy. This expansion also allowed for the exploration into preventing other drug-induced cognitive issues that may contribute to cognitive decline, such as depression.
|Date of Award||2019|
|Supervisor||Paul Gard (Supervisor)|