Bowdoin Science Journal

memory

Saffron Can Reduce Cognitive Impairment and Biomarkers of Alzheimer’s Disease

by

Saffron is a popular food condiment known to have a positive effect against neurodegenerative diseases such as dementia, Alzheimer’s, and Parkinson’s. Saffron could potentially alleviate some of the biological hallmarks of Alzheimer’s disease, including the accumulation of Aβ plaques outside of cells and neurofibrillary tangles (NFTs) inside of cells. It could also target the neurotransmitter system that involves acetylcholine (ACh), which when disrupted can lead to the progression of dementia. This system, called the cholinergic system, is essential for attention, learning, and memory. ACh plays a role in memory acquisition, encoding, and consolidation (Patel et al. 2024). 

A recent study looked at how saffron extract (CSE) supplementation affects behavioral activity, memory, Aβ plaques, and NFTs in rats. The study also investigated how saffron affects a disrupted cholinergic system. When the system breaks down, there is an increase in Aβ plaques and NFTs. There is also an increase in AChE, which is the protein that breaks down ACh. All of these factors can ultimately contribute to Alzheimer’s. The current study investigated how CSE could reduce these effects and ultimately prevent progression of dementia-related diseases (Patel et al. 2024).  

In order to study the effects of CSE, the researchers used the drug scopolamine to disrupt the cholinergic system in rats. Scopolamine mimics the memory loss observed in dementia, and it is often used to study the cholinergic system in animal models of dementia. It primarily impairs the acquisition and encoding of memories (Paul 2019). Scopolamine increases the level of AChE in the brain, which means that more ACh is broken down. With less ACh available, the cholinergic system is disrupted, causing cognitive impairments (Figure 1). The study observed the potential of CSE to reduce this disturbance. They used behavioral tests to observe memory and spatial acquisition. Blood samples and brain samples were collected for examination (Patel et al. 2024). 

Figure 1. The role of acetylcholinesterase (AChE). AChE breaks down acetylcholine (ACh) as it moves from one neuron to another. An increase in AChE leads to a decrease in ACh. (Adapted from What is the role of acetylcholinesterase at a synapse?)

The researchers found that CSE supplementation significantly improved behavioral activity and memory in rats. CSE improved performance on the reversal task, which requires the ability to switch between learned and new responses, a reflection of cognitive flexibility. 

Importantly, the study offers insight into the biological parameters that lead to the improved cognitive abilities. CSE lowered the levels of AChE, meaning that less acetylcholine was broken down. The dose of 20 mg/kg of CSE lowered the amount of AChE in the scopolamine-treated rats as significantly as Rivastigmine did (Figure 2). Rivastigmine is a pharmaceutical drug currently used to treat symptoms of Alzheimer’s by inhibiting AChE (Emre et al. 2010). An increase in the level of acetylcholine can improve memory, as demonstrated by the improved performance of the rats on the memory tests. ACh has been shown to promote nerve conduction related to memory and learning ability, helping memories get encoded and consolidated in the brain. 

Figure 2. CSE supplementation lowered the levels of AChE and inhibited its effects in rats who received scopolamine administration. Thus, less acetylcholine was broken down and disruption of the cholinergic system was attenuated. This can lead to an improvement in memory (Adapted from Patel et al, 2024). 

CSE supplementation also significantly reduced the formation of Aβ plaques and NFTs, the two classical pathological hallmarks of Alzheimer’s in the hippocampus in the brain. The 20 mg/kg dose of CSE produced the most significant reduction. CSE reduced the number of Aβ plaques and NFTs more than Rivastigmine did. In fact, the Rivastigmine group still had significant levels of NFTs and Aβ plaques (Figure 3). Accumulation of Aβ plaques and NFTs lead to neuronal dysfunction and ultimately dementia. Moreover, AChE and Aβ can bind together to form complexes that exaggerate neurodegeneration even more. Thus, if CSE can attenuate their formation, neuronal function may be preserved, preventing the progression of dementia.  

Figure 3. CSE supplementation lowered the density of Aβ plaques in rats who received scopolamine administration. This can lead to an improvement in memory (Adapted from Patel et al, 2024). 

Figure 4. Summary of the article. Scopolamine administration led to a disruption of the cholinergic system (a part of the nervous system involving acetylcholine that helps with memory and learning), neuroinflammation, and accumulation of NFT and Aβ plaques. When CSE (saffron extract) was administered, the rats’ memory improved and the biomarkers of Alzheimer’s were reduced (Adapted from Patel et al, 2024). 

Because CSE supplementation reduces the formation of Aβ plaque and NFTs in the hippocampus, inhibits the activity of the enzyme that breaks down acetylcholine, and counters neuroinflammation, a saffron-based botanical supplement could be used to help manage dementia. Currently, manufactured drugs such as donepezil and memantine have been used to treat symptoms of Alzheimer’s, but saffron could potentially offer a safer alternative that is just as effective (D’Onofrio et al. 2021). The current study tested the effects of CSE against Rivastigmine, another drug that is approved to treat symptoms of Alzheimer’s. CSE produced the same improvements as Rivastigmine. Rivastigmine, along with other chemical drugs that inhibit AChE in order to treat Alzheimer’s, has been shown to cause gastrointestinal side effects and does not have great patient compliance (Emre et al. 2010). Saffron supplementation could offer an effective treatment without such side effects, increasing quality of life. The research offers promise that saffron can improve the cognitive impairments associated with Alzheimer’s and dementia. 

 

Literature Cited

Emre M, Bernabei R, Blesa R, Bullock R, Cunha L, Daniëls H, Dziadulewicz E, Förstl H, Frölich L, Gabryelewicz T, et al. 2010. Drug Profile: Transdermal Rivastigmine Patch in the Treatment of Alzheimer Disease. CNS Neurosci Ther. 16(4):246–253. 

D’Onofrio G, Nabavi SM, Sancarlo D, Greco A, Pieretti S. 2021. Crocus Sativus L. (Saffron) in Alzheimer’s Disease Treatment: Bioactive Effects on Cognitive Impairment. Curr Neuropharmacol. 19(9):1606–1616. 

Patel KS, Dharamsi A, Priya M, Jain S, Mandal V, Girme A, Modi SJ, Hingorani L. 2024a. Saffron (Crocus sativus L.) extract attenuates chronic scopolamine-induced cognitive impairment, amyloid beta, and neurofibrillary tangles accumulation in rats. Journal of Ethnopharmacology. 326:117898. 

Paul J. 2019. Chapter 5 – Experimental Medicine Approaches in CNS Drug Development. In: Nomikos GG, Feltner DE, editors. Handbook of Behavioral Neuroscience. Vol. 29. Elsevier. (Translational Medicine in CNS Drug Development). p. 63–80. [accessed 2024 Feb 25]. 

What is the role of acetylcholinesterase at a synapse? | Socratic. Socratic.org. [accessed 2024 Mar 21]. 

Aspartame Exposure May Lead to Learning and Memory Defects

by

If you’re reading this article, you have probably had aspartame today. Aspartame, an artificial sweetener commonly found in diet sodas and other sugar-free products, is consumed by millions of people each day. Yet, there is still doubt about the safety of aspartame—even at levels well below the FDA’s recommended maximum daily intake. 

As the correlation between aspartame consumption and risk for metabolic diseases and cancers becomes more widely recognized (WHO Advises Not to Use Non-Sugar Sweeteners for Weight Control in Newly Released Guideline, 2023), it is equally important to evaluate the possible effects of aspartame on cognitive abilities. When aspartame is digested, it is broken down into phenylalanine, aspartic acid, and methanol. Phenylalanine can cross the blood-brain barrier and is a precursor of the monoamine neurotransmitters dopamine, epinephrine, and serotonin. These three neurotransmitters control memory, mood, motivation, and motor function, which may explain how aspartame affects the central nervous system (CNS).  

A study published this year in Nature sought to clarify how aspartame affects cognitive skills, specifically learning and memory abilities, and if the effects of aspartame are inheritable (Jones et al., 2023).The researchers chose to solely study male mice because there is less research concerning the heritability of cognitive defects from males.  

The researchers used three groups of mice, each with a different level of aspartame in their water: 0.015% aspartame, 0.03% aspartame, and no aspartame (the control group). These levels are equivalent to 7-15% of the FDA’s daily limit, and thus reflect the amount of aspartame many people consume per day (about 2-4 small diet soda drinks). The mice were treated for 16 weeks to evaluate the effect of long-term aspartame exposure.  

The first generation (F0) were tested for spatial working memory defects in weeks 4, 8, and 12 using a Y-Maze test. Mice have an innate curiosity to visit new arms of the maze instead of returning to ones previously visited. Hence, Y- Maze tests demonstrate the intact working memory of mice by seeing how well they remember the arms of the maze they already visited (Kraeuter et al., 2019). While there were no significant cognitive differences in the defects shown between mice of the 0.03% treatment group and the 0.015% treatment group, there were significant cognitive defects recorded for both groups of aspartame mice compared to the control group. The mice treated with aspartame were less likely to remember which parts of the Y-Maze they had already explored. However, no defects were found in relearning tasks or in learned helplessness evaluations between the groups.  

Next, the researchers tested to see if the spatial working memory defect could be paternally passed down to the next generation of mice. The mice from each of the three groups (0.015% aspartame, 0.03% aspartame, and the no aspartame group) were bred with females who had been living of off plain drinking water. However, if they mated with an aspartame-treated mouse, the females unavoidably received the same aspartame water for 1-5 days during exposure. The researchers do not believe this was enough exposure to produce aspartame defects from maternal inheritability because there was no exposure during pregnancy or lactation. When the Y- Maze test was conducted for this next generation, the spatial working memory defect found in the F0 generation was passed down.  

A third generation (F2) was also studied for possible transgenerational heritability. For this generation, the F1 mice from the 0.03% aspartame lineage and the control lineage were bred with female mice drinking only plain (non-aspartame) water. The 0.03% group was selected because it was the group with the largest exposure to aspartame, so any transgenerational effects would have been the most apparent. Nevertheless, the spatial working memory defect was not passed down across two generations.  

Because spatial learning and working memory defects were seen in the F0 and F1 generations, the researchers believe the daily aspartame consumption impacted the mice’s amygdala. The amygdala regulates emotional functions, learning, and memory (Hermans et al., 2014), and thus is one region that could explain the observed effects. However, other brain regions are involved in spatial working memory, so more research needs to be done to conclusively establish the mechanism underlying the aspartame-induced behavioral changes. 

While these results leave a lot of questions unanswered, they rightfully raise awareness concerning aspartame’s possible adverse effects. If the defects caused by aspartame are inheritable, the amount of people potentially affected by aspartame is far greater than currently recognized. The results of this study call for more research, especially on the long-term effects of aspartame at the levels people consume it. 

So, maybe be a bit more cautious the next time you reach for a diet coke! 

Literature Cited

Hermans, E. J., Battaglia, F. P., Atsak, P., de Voogd, L. D., Fernández, G., & Roozendaal, B. (2014). How the amygdala affects emotional memory by altering brain network properties. Neurobiology of Learning and Memory, 112, 2–16. https://doi.org/10.1016/j.nlm.2014.02.005 

Jones, S. K., McCarthy, D. M., Stanwood, G. D., Schatschneider, C., & Bhide, P. G. (2023). Learning and memory deficits produced by aspartame are heritable via the paternal lineage. Scientific Reports, 13(1), Article 1. https://doi.org/10.1038/s41598-023-41213-2 

Kraeuter, A.-K., Guest, P. C., & Sarnyai, Z. (2019). The Y-Maze for Assessment of Spatial Working and Reference Memory in Mice. Methods in Molecular Biology (Clifton, N.J.), 1916, 105–111. https://doi.org/10.1007/978-1-4939-8994-2_10 

WHO advises not to use non-sugar sweeteners for weight control in newly released guideline. (n.d.). Retrieved November 17, 2023, from https://www.who.int/news/item/15-05-2023-who-advises-not-to-use-non-sugar-sweeteners-for-weight-control-in-newly-released-guideline 

Retrieving Forgotten Memories With Optogenetics

by

Alzheimer’s disease is a neurodegenerative disorder in which patients experience a progressive decline in memory (Roy et. al, 2016). The early stages involve struggles to remember mostly episodic memories, which are memories of personal experiences that are linked to activity in the hippocampus. To discover potential treatments, scientists have tried to better understand the biological mechanisms behind the disease. Optogenetic activation of engram cells and calculation of dendritic spine density are two methods to research the disease. Dendritic spines are extensions from dendrites, which are the structures that receive signals from other neurons and pass them to the cell body. Memory is associated with changes in dendritic spines or the formation of new ones, which makes scientists believe that they serve as sites for memory formation and storage (Roy et. al, 2016). Engram cells are biological traces of established memories that store the information and are reactivated when memories are retrieved (Ortega-de San Luis et al., 2022). Optogenetics is a technique in which genes for light sensitive proteins are injected into specific neurons in the brain so that they can be activated by laser lights that open ion channels (Figure 1). 

Figure 1. The process of optogenetics (Adapted from Buchen, 2010). 

A 2016 study affiliated with the Massachusetts Institute of Technology used optogenetics to activate engram cells in the hippocampus of mouse models of early Alzheimer’s disease (AD) (Roy et al., 2016). With direct activation of hippocampal cells, the mice were able to retrieve the memories they had forgotten, indicating that the issue is retrieving memories; the memories are still available in the brain, but there is a problem in recalling them. Amnesia in early AD mice is also correlated with a reduction of spine density of engram cells in the hippocampus. The study showed that restoring dendritic spine density with optogenetic activation allows for the retrieval of long-term memory. Spine density was restored as the optogenetic activation allowed sodium ions to flow into the neurons and consequently depolarized them (meaning the cell is less negatively charged). This depolarization triggers long term potentiation, which is the process of strengthening connections between neurons that underlies memory and learning. Thus, restoration of spine density could lead to an effective strategy for treating memory loss in patients with early Alzheimer’s disease. 

In the experiment, the scientists labeled engram cells in the mouse models of Early Alzheimer’s disease and tested memory recall with contextual fear conditioning and long-term memory testing. Contextual fear conditioning is when mice are trained to associate a particular context (a cage) with a shock, creating a memory of the association in the hippocampus. Long-term memory was tested by placing them back into the cage and measuring their freezing behavior, a commonly used measure of fear. They also calculated dendritic spine density. 

The researchers found that optogenetic activation of memory engrams restores fear memory in early AD mice and that reversal of engram-specific spine deficits rescues memory in early AD mice. The diagram below shows the process of fear conditioning (panel t): the mice were trained to associate a shock with a certain context, and then their long term memory was tested by placing them back into the cage and observing their “freeze response,” which demonstrates that they feel fear in the cage because of the memory of the shock in the cage. The graphs show that when the engrams were activated optogenetically, the mice froze more than they did when the engrams were not activated, indicating that the optogenetic activation of the engram cells restored the mice’s memory of the fearful context. 

Figure 2. Optogenetic activation of memory engrams restores fear memory in early AD mice (Adapted from Roy et al., 2016, Fig. 1). 

The results of this study provide directions and hope for future treatments for Alzheimer’s Disease. If the amnesia is due to retrieval impairments, memory could be restored by technologies involving brain stimulation, like the optogenetic activation did in the mouse models. However, optogenetics is currently a technique only possible in animals since it is invasive, so further research will have to be done to discover a technique employing the principle in a more plausible way for humans, perhaps by finding a way to restore spine density in engram cells. There are other limitations when it comes to future treatments for Alzheimer’s because of the fact that they studied only early AD mice and episodic memory. Even though they showed that amnesia in early AD mice impairs memory retrieval, long-term memory storage in advanced stages of AD may also be impaired and eventually lost as neuronal degeneration progresses. Also, humans with early AD often exhibit non-episodic memory deficits as well, which involve brain structures outside of the medial temporal lobe that the current study did not investigate. However, overall, the findings contribute to a better understanding of memory retrieval deficits in early cases of AD, which may also apply to other neurological diseases in which patients have difficulty with memory retrieval, such as Huntington’s Disease. 

 

Literature Cited

Buchen, L. (2010). Neuroscience: Illuminating the brain. Nature, 465(7294), Article 7294. https://doi.org/10.1038/465026a

Ortega-de San Luis, C., & Ryan, T. J. (2022b). Understanding the physical basis of memory: Molecular mechanisms of the engram. The Journal of Biological Chemistry, 298(5), 101866. https://doi.org/10.1016/j.jbc.2022.101866

Roy, D. S., Arons, A., Mitchell, T. I., Pignatelli, M., Ryan, T. J., & Tonegawa, S. (2016d). Memory retrieval by activating engram cells in mouse models of early Alzheimer’s disease. Nature, 531(7595), 508–512. https://doi.org/10.1038/nature17172

Yuhas, D. (n.d.). Forgotten Memories May Remain Intact in the Brain. Scientific American. Retrieved November 4, 2023, from https://www.scientificamerican.com/article/forgotten-memories-may-remain-intact-in-the-brain/