A Step Closer to Understanding Alzheimer’s Disease

By Jenn Cook


In modern times, it seems as if there is a new, disastrous disease every year. Unfortunately though, some diseases stand the test of time with few known cures. The term ‘Alzheimer’s disease’ (AD) was first recorded in 1910 when describing patients under the care of Aloysius Alzheimer. Patients with AD exhibited early-onset symptoms, such as memory loss, disorientation, and executive function deficits (Armstrong, 2019).


A number of factors can contribute to AD, with a large number of diagnoses being due to an individual’s age. Other risks involve genetics, lifestyle, and medical diagnoses. When focusing on these, moderate-to-severe cases of traumatic brain injury (TBI) is a key risk factor for developing the neurodegenerative disease. This can be classified, where risk moderation is due to the age of occurrence, severity of injury, and number of injuries (Schaffert et al., 2018). TBI disrupts homeostatic processes and leads to an abnormal accumulation in β-amyloid (Aβ) and tau, which are the main protein identifiers of AD. This homeostatic dysfunction can lead to an early-onset AD diagnosis of at least 3 years. There is not yet a clear and distinct understanding of how TBI is directly tied with AD, though researchers have tried in discovering a clear mechanism. Thankfully due to modern technological advances, research on Azlheimer’s has been all but stagnant.


Researchers have observed relationships between TBI and AD when using human and animal models. A revolutionary study conducted in 2018 was the first to examine AD-like characteristics in behavior and biochemistry in transgenic mice strains for the human tau protein. These proteins are typically involved in stabilizing the structure of cells (Zhang et al., 2019). Since the concentration of tau exponentially increases post-injury, the researchers hypothesized that this aggregation will result in AD-like physiology with similarly-presenting symptoms. Whereas the mice in the control group did not have any injury, the mice in the test group received controlled cortical impact (CCI) surrounding the left hippocampus, the brain region best associated with memory. Approximately three to six weeks following the trauma, the mice performed in tests to assess for deficits in locomotion, learning, and memory. Researchers then analyzed cortical slices to determine tissue abnormalities in within the hippocampus that could contribute to AD-like symptoms over time. Though tau growth was the main focus of the study, the researchers searched for manipulations in similar proteins identified as AD biomarkers [e.g. glial fibrillary acidic protein (GFAP)].


Upon observing the results from a behavioral perspective, Zhang and colleagues (2019) discovered overall impairments in learning, memory, and locomotion. Through the use of a rota-rod test, where rodents are placed on a rotating rod to enforce movement, it was found that the CCI mice had decreased motor activity in comparison to the sham group. When observing any alterations for learning and memory, a novel object recognition test demonstrated a reduction in discrimination between the novel and familiar objects in CCI mice, showing their inability to remember objects previously presented to them. In a similar sense, these mice were incapable of locating the target platform in a Morris water maze. This explained deficits in spatial memory, where the mice cannot form memories on spatial orientation.


An explanation for the cognitive deficits in the CCI mice is the abnormal concentration of the tau protein discovered in the left hippocampus (Zhang et al., 2019). A slight increase was observed six weeks after impact, though this data was not statistically significant. On the other hand, GFAP expression increased in the hippocampus, where researchers found a rise in reactive astrocytes. The importance of this particular finding is because astrocytes are a subtype of cells in the brain that are typically involved in the regulation of neurons (Osborn et al., 2016). When these functions go awry, astroglia release proinflammatory proteins that lead to swelling in axons. Once the axons are damaged, there is an influx of the Aβ proteins, that can cause a reduction in cortical regions, alongside with the tau tangles.


It is difficult to implement only one type of treatment for TBI, as there are a number of factors and proteins involved with the severity of cortical damage. A novel method, however, is dependent on the fatty acid inhibitor, PF04457845. This inhibitor was injected in the cortex of CCI-induced mouse models to assess for potential reversible damage (Selvaraj et al., 2019). It was discovered that PF04457845 decreased neuroinflammation, along with tau and Aβ accumulation. This treatment even improved deficits in locomotion and memory. Though this was tested in mouse models, it proved good face validity, where it measured what it was intended to, and translates well to human studies. If this is the case, then this discovery will bring more evidence to the hypothesis that neuroinflammation plays a larger role in TBI and AD than people think.


The findings in this study push science further towards a successful treatment for individuals diagnosed with AD. Additionally, it exposes further predispositions, which with enough research, can actually decrease the amount of people that experience AD-related symptoms. Whether introduced through TBI or other means, this research is an incredible breakthrough in neuroscientific research. In 2019, this article initiated a more hopefully future for treating, and ideally, eventually curing Alzheimer’s. The next decade is full of hope of the future of science.


References:


Armstrong, R.A. (2019). Risk factors for Alzheimer’s disease. Folia Neuropathologica, 57(2), 87-105. Doi: 10.5114/fn.2019.85929.


Osborn, L.M., Kamphuis, W., Wadman, W.J., & Hol, E.M. (2016). Astrogliosis: An integral player in the pathogenesis of Alzheimer’s disease. Progress in Neurobiology, 144, 121-141. Doi: 10/1016/j.pneurobio.2016.01.001.


Schaffer, J., Lobue, C., White, C.L., Chiang, H.S., Didehbani, N., Lacritz, L., … Cullum, C.M. (2018). Traumatic Brain Injury History Is Associated With an Earlier Age of Dementia Onset in Autopsy-Confirmed Alzheimer’s Disease. 32(4), 410-416. Doi: 10.1037/neu0000423.


Selvaraj, P., Wen, J., Tanaka, M., Zhang, Y. (2019). Therapeutic Effect of a Novel Fatty Acid Amide Hydrolase Inhibitor PF04457845 in the Repetitive Closed Head Injury Mouse Model. Journal of Neurotrauma, 36(10), 1655-1669. Doi: 10.1089/neu.2018.6226.


Zhang, Y., Wi, F., Iqbal, K., Gong, C.X., Hu, W., & Liu, F. (2019). Subacute to chronic Alzheimer-like alterations after controlled cortical impact in human tau transgenic mice. Nature, 9(1), 1-13. Doi: 10.1038/s41598-019-40678-4.

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