Alzheimer's and Beta Amyloid: A Complicated Relationship

In the impressive piece by Dr. Roberto Fernandez titled Early Alzheimer’s disease blocks responses to accelerating self-movement and the subsequent presentation, Dr. Fernandez thoroughly explained the progressive pathology of Alzheimer’s disease (AD) as well as his desire to find pathological markers to outline its development within the human brain. He began by explaining that this neurodegenerative disease is most prevalent in the population above 65 years of age with dementia being the prominent hallmark of diagnosis.

In explaining the basis of AD, he presented some of the pathology behind the disease which is currently known. Dr. Fernandez, in his presentation, dictated how Beta Amyloid and Tau are both proteins that are responsible for maintaining microtubule structure and transport of materials via tubules but when these proteins become abnormal, they form plaque within the brains of AD patients. This plaque subsequently blocks transmission at synapses resulting in inhibition of brain activity. It was also noted that plaque formation often begins in the medial temporal lobes (memory center of the brain) and the progress towards the parietal and frontal lobes which is often why dementia is an early sign of Alzheimer’s.

What was most interesting, however, is his explanation of the visuospatial symptoms that are prevalent in over 1/3 of AD cases. He explains that visual processing of day to day life often involves the ventral region of the brain, which is responsible for face identification for example, and the dorsal region, which is used for attaching meaning to locations of objects. He stressed this fact as the information from these two regions are used to form different networks and when posterior cortical and parietal atrophy begins to appear, the degeneration of these networks occurs. In order to test this network degeneration, he ran a set of experiments in which he had subjects from a wide age range and with differing stages of AD perform simulated driving tests where one would have to remember how to get to and from certain locations after being given initial instruction. Dr. Fernandez observed the number of memory errors and accident that occurred within the simulator to test the subjects’ ability to create and retain a temporary visuospatial memory map. The way he quantified his test was by giving the example of how AD patients would often be suddenly unable to remember how to get to a store from their home and back, after having done so a multitude of times because of this degradation of neural networks. His goals for the experiment were to attempt to find markers of network degradation in AD by age and AD stage by correlating these descriptors to the number of errors in the simulator.

Still, Dr. Fernandez also explained that much is still not known about the pathogenesis of Alzheimer’s disease with many scientists still wondering how the dysfunction of the aforementioned proteins causes synapse degradation or why exactly the disease is more prevalent as age progresses, for example. However, scientists at the Stanford School of Medicine have presented work that claims Beta Amyloid dysfunction is not the sole reason for network degradation in the brain. While scientists are looking for pharmacologic methods to rid the brain of Beta Amyloid, Dr. Carla Shatz is looking for methods by which to protect synapses from being inhibited by the protein instead.

Dr. Shatz claims that AD “starts to manifest long before plaque formation” and has found that as Beta Amyloid begins to develop into plaque, it forms small clusters that are soluble and travel in the brain which eventually binds strongly to a receptor on neurons that begins a process where synapses with other nerve cells are eroded. In her experiment, she used strains that were highly susceptible to the impairments of AD and found that a receptor protein named PirB with high affinity for Beta Amyloid in the soluble form began the aforementioned erosion process. In continuing her research, Dr. Shatz utilized mice that lacked PirB and were highly susceptible to AD which led to her observing mice with high levels of Beta Amyloid protein but no neurodegenerative effects. The question of why this observation is occurring is still being found.

In the end, Dr. Fernandez may be able use the aforementioned research to finally find the markers for AD progression he was looking for. It is possible that while his subjects may have had a wide range of Beta Amyloid concentrations in their brain tissue, the reason behind their dementia and neurodegeneration may be the receptor proteins that bind the abnormal Beta Amyloid rather than simply the age of the patient.

Works Cited

1)     Fernandez, Roberto, and Charles J. Duffy. “Early Alzheimer's Disease Blocks Responses to Accelerating Self-Movement.” Neurobiology of Aging, vol. 33, no. 11, 2012, pp. 2551–2560., doi:10.1016/j.neurobiolaging.2011.12.031.

2)     Goldman, Bruce. “Scientists Reveal How Beta-Amyloid May Cause Alzheimer's.” Stanford University School of Medicine, 19 Sept. 2013, med.stanford.edu/news/all-news/2013/09/scientists-reveal-how-beta-amyloid-may-cause-alzheimers.html.

3)     Hamley, I. W. “The Amyloid Beta Peptide: A Chemist's Perspective. Role in Alzheimer's and Fibrillization.” Chemical Reviews, vol. 112, no. 10, 2012, pp. 5147–5192., doi:10.1021/cr3000994.