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Hi there!
Hi there!
My name is Sofia Lombard. I am a senior at Clarkstown High School North who is passionate about neuroscience. This is my third year in the science research program. Last summer, I had the opportunity to intern at Massachusetts General Hospital under the Genetics and Aging Research Unit (GARU), a division of Harvard Medical School dedicated to searching for an Alzheimer's disease cure. Let’s take a closer look at the research I’ve been conducting and how it all started…
First off, a little about myself :)
First off, a little about myself :)
I am an avid two-sport athlete and have been playing ice hockey for 10 years now! In my free time, I love to snowboard, create films, take pictures for my scrapbook, and eat sushi.
Behind the scenes on set!
MY SCIENCE RESEARCH JOURNEY
During my sophomore year of high school, I decided to take the Science Research class, a 3-year college course dedicated to developing research skills and investigating your own topic of interest! I started researching advances in stem cell therapies and their veterinary medicine applications, but I realized that this topic didn't quite interest me as much as I thought it would. During this period, however, I found that ophthalmology intrigued me. I decided to branch away from researching stem cells and focused on inherited eye disorders, retinal degeneration, and the role of oxidative stress. Consequently, I discovered the overlapping pathologies between brain and eye disorders, which ultimately led to my current research in Alzheimer's disease.
The Role of Nanoparticles in the Treatment of Iron Overload Induced Neurological Disorders
The Role of Nanoparticles in the Treatment of Iron Overload Induced Neurological Disorders
Alzheimer's disease, Parkinson's disease, and hereditary hemochromatosis all share similar pathogenic pathways. Abnormalities in iron metabolism and other redox-active metals bind to excessive deposits of amyloid β and p-tau plaques. This, in turn, triggers neuroinflammation and degeneration. I began by researching the use of nano-chelators as a clinically relevant therapeutic option for treating neurological disorders. These nanoparticles can help mobilize iron in the brain, preventing toxic overload while promoting iron absorption into deficient cells. My specific focus was on a small, natural molecule called hinokitiol that can mimic protein-like functions in cells.
MY INTERNSHIP EXPERIENCE
Evoking Gamma Waves to Induce Microglial Phagocytosis of Amyloid
Alzheimer's disease is a brain condition that can develop in elders, impacting one’s memory, cognition, and ability to perform basic tasks. Over time, as the brain begins to age, amyloid plaques build up, which triggers immune cells in the brain called microglia to become inflammatory. These changes can lead to widespread neuronal dysfunction, facilitating cell death and neurodegeneration.
The researchers at Mass General have found that inducing a certain wavelength of light on the brain had therapeutic effects on reducing amyloid plaques. After the therapy was completed, amyloid plaques from the mouse brains were analyzed using a computer software. Not only were plaque concentrations greatly decreased, but the amount of microglial cells that were “eating” the plaques had also increased, both of which were promising signs for this treatment method. Yet, the specific connection between inducing gamma brain waves in the basal forebrain and the microglial activation occurring elsewhere in the brain remains unclear.
Sorting brain tissue for histology
My Involvement
My Involvement
At Mass General, I was a part of the research team's project every step of the way, from creating pipettes, observing mouse brain surgery, slicing and preparing brain tissue for histology, running ELISA tests, using flow cytometry, and analyzing plaque counts with unbiased stereology.
Micro-thin brain tissues that I sliced (roughly 40 microns wide, which is smaller than a human hair!)
Arranged slices from the anterior to the posterior of the brain. This organization is done before mounting the slices onto coverslips
Here is an image of a brain slice that is mapped onto the computer using a software called NeuroInfo. The neon flourescent marks highlight the basal forebrain, the area where gamma oscillations are generated.
CURRENT PROJECT
The Effect of Gamma Brain Waves on the Glymphatic System, AQP-4 Localization, and Astrocytes
Background:
Gamma oscillations, associated with many cognitive processes, are primarily generated through GABAergic inhibitory neurons. In cortical regions, fast spiking Parvalbumin (PV) neurons, which are inhibitory, project onto glutamate pyramidal neurons, which are excitatory. With these mechanisms in hand, targeting basal forebrain PV neurons may be a therapeutic approach for Alzheimer’s disease, as it is clear that they can activate and regulate gamma production by entraining the cortical oscillator at 40hz stimulation. Optogenetics, as used by the Tsai lab, demonstrated that 1 hour of 40hz flickering light stimulation helped recruit microglia and lower A β140 and A β1-42 levels, meaning that entraining gamma oscillations in the mouse brain can help promote greater amyloid/microglia interactions and lower plaque levels. However, it remains unclear how this connection in the brain is working. What pathological changes induced by the gamma entrainment are causing M2 microglia to become activated?
The glymphatic system, a waste disposal method, is the exchange between the central spinal fluid (CSF) and the interstitial fluid (ISF). It is heavily influenced by cortex-wide neuronal activity, mainly REM sleep. AQP-4, the most abundant water channel in the brain found on astrocytic end-feet, is essential to the glymphatic clearance network function. This protein facilitates water diffusion and transport throughout the brain, a process that is essential for neuronal activity. AQP-4 also plays a role in neuroexcitation, astrocyte migration, memory, and synaptic plasticity. However, in Alzheimer’s disease, AQP-4 is abnormally expressed and mislocalized away from astrocytic end-feet. This can lead to the depolarization of AQP-4 and astrocytes, lowering CSF-ISF flow and causing a greater accumulation of toxic amyloid plaques. In mouse tissue, rich AQP-4 stains were found within the reticular thalamic nucleus, a GABergic structure, suggesting a potential relationship between gamma production, AQP-4 localization, and Alzheimer’s disease.
Hypothesis:
Evoking 40hz gamma waves in the 5xFAD mouse model will increase AQP-4 and astrocyte co-localization, resulting in greater glymphatic clearance of amyloid plaques.
Open Box Science
Literature Review:
FUTURE PLANS
Currently, I am designing my own experimental study, investigating the effect of gamma brain waves on the glymphatic system in Alzheimer's disease. I am working closely with my mentor from Mass General to devise a complete research plan, including an introduction, hypothesis, materials/methods, and laboratory protocols. In the spring, I plan on returning to Mass General to collect data, analyze the results, draw conclusions, and publish the paper.
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