In Beth Stutzmann’s work she uses AD mice models in hopes to identifying early signs of Alzheimer’s. In one paper she discusses different processes that affect Ca+2 (Ca) signaling and their role in Alzhiemer’s disease. Ca signaling is important due to its role neurotransmitter release. If Ca is blocked release is inhibited because without Ca vesicles are not able to separate from synapsin. Increased Ca within the cell inhibits this process by changing the concentration gradient, now more inside than outside, which reverses the normal flow of Ca upon opening of the voltage-gated Ca channels. This decrease in vesicle release causes a decrease in plasticity which is involved in learning/memory. One way Ca is increased is through Aβ peptide increase because they make more Ca permeable channels on the plasma membrane. Increased Ca through RyR3 mediation leads to more Aβ peptides but also Aβ plaque formation. Increase Aβ can also increase RyR3 expression furthering this relationship. APOE gene codes for production of apolipoprotein E, which function is combining lipids for formation of lipoproteins. One variation of this gene, ɛ4, increases intracellular Ca levels by recruiting the plasma membrane channels and RyR-mediated ER stores. APOE is also thought to regulate the formation of Aβ plaques, ɛ4 being bad at preventing their formation.
In another paper she studies nitric oxide’s role in sustaining synaptic plasticity. Due to the “abnormal synaptic function” that is observable before cognitive deficits are, synaptic plasticity is gaining recognition as a cause to the memory impairments of Alzheimer’s. Since synaptic function is altered before cognitive functions they conclude that there must be something compensating in order to keep cognitive functions normal. In this she looks at suppression of RyR-evoked Ca signaling, causing intracellular to increase since RyR regulates the release of Ca. Stutzmann’s research suggest nitric oxide (NO) as a candidate for the “compensatory mechanisms [that] are recruited to maintain a functionally normal net output of the hippocampal circuit”. Both of these papers contribute to finding early warning signs and possible markers that can be used in the diagnosis of AD.
In Stutzmann’s presentation of her research she gave some insight as to why science is at a standstill in terms of finding a cure. Two reason she listed were that research is focusing on late AD processes and that studies consistently use/target the same areas. Another challenged mentioned was that unlike diseases such as Huntington’s disease, Alzheimer’s does not have clear identifiable genetic markers. This unknown genetic cause contributes to the issue because the knowledge of what causes this disease genetically would allow us to focus on the chemical aspects of the disease and monitor their levels. This could help in identification and treatment of early stage Alzheimer’s.
In an article on Scientific American (Nature on Aug. 1 2017) by Sara Reardon discussed biological makers, which are thought to contribute in the development of Alzheimer’s, are found in chimpanzees. Specifically, the three markers discussed are plaques, tangles of proteins, and the loss of neurons. The amyloid-β and tau proteins, what causes plaques and tangles respectively, found in chimps are identical to those in humans. They looked at 20 chimps’ brains, examining brain regions that are damaged during AD. Pre-tangles were found in all 20, four had plaques and tangles, and “several of the chimp brains contained amyloid-β”. Regardless of similarities, researchers found no evidence of severe dementia and could not link biological changes to changes that occurred in chimp brains. William Hopkins, co-author, suggest that these markers present the opportunity for dementia to happen. One explanation for this is the idea of a protective factor within chimps. Two theories discussed as possible reasons for this contrast are; the protein markers, amyloid-β and tau, may fold differently in chimpanzees and/or the different behavior of APOE between the two species. Alzheimer’s, a progressive neurodegenerative disorder caused by neuron death, is effected by the protein markers through their suggested contribution in cell degradation. One piece of evidence for different folding of these proteins mentioned within this article is due to finding amyloid-β in the brains studied. Amyloid-β is more commonly found outside of blood vessels in humans, however the presence in brains “suggests that plaques may form in a different way in chimps”. The article specifies the function of APOE as controlling “how amyloid-β aggregates into plaques”, because this is its suggested role in AD development. Within humans the APOE gene has three alleles (ɛ2, ɛ3, ɛ4) but in terms of AD development APOE ɛ4 is the relevant allele. APOE ɛ4 is purposed to increase risk of Alzheimer’s by not being as effective as the other alleles in break-down of the plaques. Essentially the absence of dementia could be from the different folding of proteins, meaning plaques never form, and/or the better functionality of APOE in chimps, a more effective break-down of possible plaques. Prior to these findings humans were thought to be the only primates where plaques and tangles occur simultaneously. Reardon reported that Elizabeth Head, a neuroscientist at the University of Kentucky in Lexington said “Even if chimps never develop the symptoms of Alzheimer's, knowing that they spontaneously develop biological signs of the disease could yield useful information about its early stages and potentially how to prevent it” Mary Ann Raghanti, conductor of the brain analyses, says “If we could identify the things that are similar and different in chimpanzees and humans, we can start to unlock why humans are so uniquely susceptible to this pathology”. From these findings future steps, which Raghanti says are now being done, in their studies include examination of inflammation and neuron loss with age which are two other important factors to AD.
Both these studies discuss the APOE and plaques possible roles in AD. Unlike Stutzmann, Raghanti did not get to observe the brain activity of these chimps which greatly limited her research. I would be interesting to see the role of Ca had with chimp synapses. If two studies such as these were to come together, NO testing in a chimp brain, many strides into the working of these processes could happen. Useful information that could come through further studies of chimpanzees are; potential of identifying a protective factor, determine cause of dementia development, and better caretaking of chimpanzees. However, since 2015 biomedical research on chimps has ended, including MRI scans. This obviously prevents most studies that can been done in relation to AD and chimps but if betterment of chimpanzee life is considered and emphasized maybe there is a chance for exceptions to be made. At least in regards to scans being performed on chimps while they’re alive to get more accurate information on possible degeneration.
- Chakroborty, Shreaya, and Grace E. Stutzmann. "Early calcium dysregulation in Alzheimer’s disease: setting the stage for synaptic dysfunction." Science China Life Sciences 54.8 (2011): 752-762.
- Chakroborty, Shreaya, et al. "Nitric oxide signaling is recruited as a compensatory mechanism for sustaining synaptic plasticity in Alzheimer's disease mice." Journal of Neuroscience 35.17 (2015): 6893-6902.
- Reardon, Nature Sara. “Chimpanzees Are First Animal Shown to Develop Telltale Markers of Alzheimer's Disease.” Scientific American, 1 Aug. 2017, www.scientificamerican.com/article/chimpanzees-are-first-animal-shown-to-develop-telltale-markers-of-alzheimers-disease1/.
