The Effects of Amyloid Beta on Neuronal Transcription

Overview

Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder, associated with a decline in cognition and impaired episodic memory. Globally, it has been estimated that 26.6 million people are afflicted with AD. This disorder is well known for its behavioural phenotype, however knowing its cellular pathology, which is primarily based on the presence of Amyloid β (Aβ) in various aggregation states, is crucial for the development of research efforts against the disease. The most notable of these aggregation states are the oligomeric (oAβ) and fibril (fAβ) forms. Despite the understanding that this protein is the defining characteristic of the disorder, there is still debate as to whether Aβ is the cause of the deleterious effects, or whether it is a symptom of a further underlying cause of the disorder.   

As such, this project aims to determine what the downstream effects of Aβ are on neurons and by doing so illustrate what deleterious effects Aβ causes. To accomplish this goal the transcriptomic profile of neuronal cells exposed to these aggregation states of Aβ was quantified.

Our primary findings illustrate the significant effects of Aβ on genes associated with metabolism as well as the dramatically increased effects of oligomeric Aβ relative to fibril Aβ with respect to the overall changes in gene expression. These results also support the further examination of the role of GTPases in the negative effects of Aβ. Observed changes in glucose metabolism and utilization may be a direct result of Aβ deposits, and as such strengthens the hypothesis that neuronal damage due to decreased energy consolidation is directly caused by Aβ rather than Aβ deposits being an effect of said changes in glucose utilization.  Our results also show that Aβ can dysregulate glutathione metabolism. Glutathione is a cellular antioxidant and therefore alterations in the genes associated with its metabolism can lead to decreases in the reduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The hypothesis of Aβ causing oxidative stress through glutathione is also supported by the changes in Rho-GTPase signaling.

Considering the presented research illustrates alterations in both membrane trafficking and signaling molecules, the downstream effects of Aβ may offer a potential explanation for the disruption of the proper function of these neurotransmitter systems. The presented research shows that Rho-GTPases are disproportionally affected by Aβ and considering the role of these proteins in the formation and function of the synapse, this also suggests that neurotransmission deficits can be attributed directly to Aβ. This is especially notable as it seems that Rho-GTPases are vital for long-term potentiation linking their disruption to the most well-known side effect of AD, namely decreased memory consolidation.