Preventing Cognitive Decline through implementation of Hippocampal-derived Leptin paired with Exercise and Antioxidant Rich Diet

As neuroscience students, we always learn of how terrible and debilitating Alzheimers disease can be. In fact, there have been about 23,000 research papers published concerning this disease over the past two decades with little progress in treating or fully understanding it (Greger 2018).We are certain to learn the biology of this disease such as beta-amyloid plaques, neurofibrillary tangles, and the gene ApoE4 that increases your chances of getting the disease. However, how often are we told and/or taught about Alzheimer's nutritional etiology...never? According to studies 1, 2, and 3, several autopsies of Alzheimer's patients revealed significantly more atherosclerotic plaque and narrowing of cerebral arteries. This consequence is due to the unusually high consumption of processed foods, dairy, and meat products in the United States. A Harvard Women's study revealed that consumption of higher saturated fat from these foods led to overall decline in cognition and memory, which are the key pathologies of Alzheimer's disease (4). Given that our brain uses almost 50% of the oxygen we breathe, it only makes sense to presume that our brain is a prime target for damage from free-radicals and reactive oxygen species(ROS). These ROS's and free radicals can lead to cellular damage, aging, and death. The reasonable solution would be to recommend consuming large sums of antioxidants found in berries, leafy greens, and other whole foods. To much success, this recommendation is a large contributor in reducing Alzheimer's disease, cancer and heart disease. Polyphenol, one of many antioxidants found in berries, "has been shown to protect nerve cells in vitro by inhibiting the formation of plaques and tangles that characterize Alzheimer's,"(Greger 2018). While this information is great, the question still remains, are there any internal mechanisms that are able to slow the spread of such diseases? Dr. Hideaki Soya's 2019 paper "Leptin in hippocampus mediates benefits of mild exercise by an antioxidant on neurogenesis and memory," would say yes. 

One of the key unknown ideas discussed in Dr. Beshel's 2017 paper was the unknown physiological role that brain-derived leptin plays in the body. While Leptin derived from adipose tissue plays a role in satiety signaling, hippocampal-derived Leptin has been shown to "enhance adult hippocampal neurogenesis and synaptic function, which facilitates spatial learning and memory function, suggesting a neurotrophic role of Leptin within the hippocampus, "(Soya et al. 2019). With the positive effects of antioxidants and exercise seen in rodent cognition and memory, Soya et al., decided to test these metrics in relation to hippocampal-derived Letpin. More specifically, they discovered that hippocampal Leptin mediates the beneficial effects of antioxidants and exercise on hippocampal neurogenesis and memory. The three seem to exhibit a synergistic relationship all resulting in up-regulation of brain-derived Leptin genes. Furthermore, Soya et al. measured the effect of infusing Leptin on obese mice lacking hippocampal Leptin. To test this, they used the Morris Water Maze (MWM) assay where the mice were timed of how long they remained in a desired region called the Platform zone. The mice's paths taken to reach this zone were also tested to determine where the mice spent the majority of their time in the maze. 

Figure 5. Central LEP involved in ME +AX-induced enhancement of spatial memory in LEP-deficient mice.

In Figure 5G, you can see that injection of LEP while the mice were given AX and ME resulted in increased time on the platform, which is an indication of the mice learning to navigate the maze. In addition, in 5F, you can see that LEP injected mice had a much more contained path as they were able to better learn their spatial environment. So, what does this mean practically? These data show that a lifestyle stressing the importance of antioxidant-rich diet and moderate exercise is a means to increase cognition and slow cognitive decline. It also offers a potential avenue in slowing and/or preventing neurological diseases such as Alzheimer's. If this lifestyle is able to offer a few more years of cognitive abilities to the aging population, then it is something that should be emphasized in all stages of life.

References:

Beshel, Jennifer, et al. “A Leptin Analog Locally Produced in the Brain Acts via a 

Conserved Neural Circuit to Modulate Obesity-Linked Behaviors in 

Drosophila.” Cell Metabolism, vol. 25, no. 1, 10 Jan. 2017, pp. 208–

217., doi:10.1016/j.cmet.2016.12.013.

Yook, J., Rakwal, R., Shibato, J., Takahashi, K., Koizumi, H., Shima, T., . . . Soya, H. (2019, May 28). Leptin in hippocampus mediates benefits of mild exercise by an antioxidant on neurogenesis and memory. Retrieved October 16, 2020, from https://www.pnas.org/content/116/22/10988

“How Not to Die from Brain Diseases.” How Not to Die: Discover the Foods Scientifically Proven to Prevent and Reverse Disease, by Michael Greger and Gene Stone, Pan Books, 2018, pp. 51–57.

1. Roher AE, Tyas SL, Maarouf CL, et al. Intracranial atherosclerosis as a contributing factor to

    Alzheimer's disease dementia.  Alzheimers Dement. 2011;7(4):436-44

2. Yarchoan M, Xie SX, Kling MA, et al. Cerebrovascular atherosclerosis correlates with 

    Alzheimer pathology in neurodegenerative dementias. Brain. 2012;135(pt.12):3749-56.

3. Honig LS, Kukull W, Mayeux R. Athersclerosis and AD: analysis of data from the US National 

    Alzheimer's Coordinating Center. Neurology. 2005;64(3):494-500. 

4. Okereke OI, Rosner BA, Kim DH, et al. Dietary fat types and 4-year cognitive change in community-dwelling older women. Ann Neural. 2012;72(1):124-34.