Recent research has increasingly pointed to modifiable lifestyle factors as powerful tools for reducing dementia risk. Among these factors is diet, with intermittent fasting gaining significant attention for its potential to lower Alzheimer’s risk. This approach focuses on timing rather than caloric restriction—strategically alternating between periods of eating and fasting by consuming normal daily calories within a specific window. A common strategy involves a 16-hour fast followed by an 8-hour feeding window. Research in mouse models, including those that produce toxic levels of amyloid and tau, suggests that intermittent fasting may benefit the brain by improving mitochondrial function and brain plasticity—the strengthening of connections between neurons that support learning and memory. Similar beneficial brain effects are seen in humans. However, restricting eating to specific windows can be challenging and not medically appropriate for everyone. Therefore, a drug that mimics the benefits of intermittent fasting without requiring strict fasting schedules could make it easier for people to manage their risk of Alzheimer’s disease (AD).
Drs. Ratan and Lampidis are working with one such drug, 2-deoxyglucose (2-DG), that mimics intermittent fasting. 2-DG is an analog of glucose—similar enough in structure that cells readily use it as a substitute. However, because it is slightly different, it blocks the normal metabolism of glucose. Since cells cannot use their preferred fuel, they must find alternative energy sources, just like during fasting. This triggers a cascade of cellular responses that ultimately activate similar but not identical beneficial pathways that make intermittent fasting promising for health.
In an amyloid mouse model, Dr. Ratan and his colleagues found that 2-DG improved synaptic transmission—how neurons communicate information between each other—and cognitive performance. These benefits likely resulted from the activation of a well-known brain plasticity gene called brain-derived neurotrophic factor (BDNF). Previously, it had been thought that the ketone beta-hydroxybutyrate (BHB) produced during intermittent fasting was required for BDNF to be induced to confer its beneficial effects on brain function. However, the Ratan lab was able to show that 2-DG could produce BDNF without inducing BHB. They discovered a mechanism of action: when sugar levels in cells drop, whether due to intermittent fasting or 2-DG treatment, a process called N-linked glycosylation, where sugar molecules are attached to proteins to change their function, is interfered with. This triggers stress in the endoplasmic reticulum (ER; the cell’s protein factory), which in turn signals a protective response, activating genes involved in brain plasticity, repair, and maintenance. Building on these findings, Drs. Ratan and Lampidis hypothesized that 2-DG will also protect against tau-mediated pathologies by inducing the same beneficial ER stress response to enhance brain plasticity while limiting neurodegeneration.
They proposed two experimental aims to test this hypothesis: In the first aim, they are determining the optimal dose of 2-DG needed to induce ER stress and increase BDNF expression and then confirming that this triggers the expected protective effects. They are injecting 2-DG daily for three months into tau (PS19) mice, starting before neurodegeneration occurs. To verify the treatment works as expected, they are measuring multiple outcomes: activity of protein kinases and ATF4 (a stress-responsive transcription factor controlling neural plasticity and repair genes), potential blood biomarkers using single-nucleus RNA sequencing, learning and memory through behavioral tests, synaptic strength via electrophysiology, and tau pathology and synapse number in brain tissue.
In the second aim, they are conducting similar experiments, but this time using two 2-DG analogs: 2-FDM and 2-FDG, which Dr. Lampidis has shown to have differential effects on glucose metabolism in cancer cells. Based on their understanding of these differential effects, they expect that 2-FDM, a mannose analog, will also induce the ER stress response and increase BDNF, albeit at lower concentrations than 2-DG. After establishing optimal doses of 2-FDM and 2-FDG in tau mice, they will conduct behavioral tests, examine synaptic function, and quantify BDNF expression, tau burden, and synapse number. Through these steps, they hope to uncover the potential benefits of these compounds in treating AD pathologies as well as to better understand the mechanisms by which 2-DG produces beneficial effects on brain function.
In the first year of funding, Drs. Ratan and Lampidis established the mouse colonies for this study and performed experiments to verify the biological effects of 2-DG in the tau mice. To their surprise, their usual route of administration (a single injection into the abdominal cavity) did not increase BDNF levels or induce ER stress in the tau (PS19) mice like it did in other mouse models. This prompted them to explore alternative delivery methods, and they changed to Alzet pumps, which are implanted into the mice and continuously deliver 2-DG. While waiting for data from these studies, they shifted to microglial cell cultures and found that 2-DG and its analogs inhibited the inflammatory STING pathway, which suggests that 2-DG exerts its beneficial effects differently in neurons and microglia. In neurons, 2-DG increases protective neurotrophic factors, such as BDNF, while in microglia, 2-DG helps limit neuroinflammation. This latter finding could have profound effects in controlling inflammation, which is a contributing factor to the pathology associated with Alzheimer’s, as well as in other diseases. The second funding period will focus on completing the mouse experiments and exploring the cell-type-dependent effects of 2-DG and its analogs, ultimately leading to the selection of the one that best benefits Alzheimer’s patients.
