Alzheimer’s disease (AD) develops gradually, beginning long before memory loss or other symptoms appear. Scientists know that two proteins, amyloid beta and tau, misfold and accumulate in the brain, damaging nerve cells and disrupting communication between them. Tau, in particular, plays a major role in this process, and its abnormal buildup spreads through the brain in a pattern that mirrors the progression of cognitive decline. However, it remains unclear how this spread begins and what cellular changes make some brain cells more vulnerable than others.
Dr. Bloom and Dr. Norambuena have long focused on understanding how small, toxic clusters of tau, known as extracellular tau oligomers (xcTauOs), damage brain cells at the molecular and cellular levels. Their previous work found that when neurons encounter these toxic tau forms, a specific mitochondrial metabolic pathway, the NADK2–NADPH–Proline pathway (NPP), becomes abnormally active. This pathway typically helps generate molecules that support energy balance and protein synthesis, but when overactivated, it triggers a cascade of harmful metabolic and structural changes that make neurons more susceptible to tau toxicity. The team found that xcTauOs activate this pathway both in cultured human neurons and in the brains of tauopathy model mice (PS19), even before symptoms emerge.
Preliminary experiments showed that when neurons are exposed to toxic tau, the enzyme NADK2 becomes unusually active. NADK2 acts like a switch that controls how mitochondria, the cell’s power plants, convert nutrients into energy and protective molecules. When this switch is repeatedly flipped on, the cell’s energy production becomes unbalanced. Instead of fueling normal repair and cleanup processes, it starts generating stress signals that damage the cell from within. The team found this same overactivation pattern in both neurons and human microglia, suggesting that tau pushes these cells into an unhealthy, overworked state. Together, these results point to mitochondrial stress caused by tau as an early and potentially reversible step in Alzheimer’s development. Building on these discoveries, Drs. Bloom and Norambuena hypothesize that xcTauOs hijack this same mitochondrial pathway in microglia, converting them from protective immune cells into drivers of neuroinflammation and tau spread. Microglia usually act as the brain’s cleanup crew, clearing away harmful proteins like amyloid and tau. But when their internal energy systems stop working properly, these cells can switch roles—fueling inflammation and cell damage instead of preventing it.
To test this hypothesis, the investigators will pursue two experimental aims. In Aim 1, they will determine how toxic tau oligomers activate the NPP pathway in human microglia. Using advanced live-cell imaging and metabolic assays, the team will measure changes in mitochondrial activity and quantify NADK2 and related enzymes in human stem cell–derived microglia. They will also manipulate these enzymes with genetic tools to define which steps in the NPP pathway are essential for tau-induced metabolic stress, and have now expanded these studies to compare how tau oligomers made from each of the six human tau isoforms affect this pathway, providing a fuller picture of how different forms of tau may drive disease. In Aim 2, they will examine whether these metabolic changes influence how microglia take up, process, and spread tau. The researchers will assess tau uptake and clearance in cultured human microglia with or without NADK2 expression and then extend these experiments into tauopathy mouse models. New preliminary data showing that a modest reduction of NADK2 in PS19 mice lowers NPP activity and decreases harmful tau species without obvious side effects strengthens the feasibility of this approach. In response to reviewer suggestions, the team will also test whether FDA-approved drugs such as memantine or metformin can safely modulate this pathway in human cells. Finally, they will broaden their analysis in mouse tissue by examining NADK2 and related enzymes across multiple brain regions that are vulnerable in AD. By combining genetic and pharmacological approaches to rebalance microglial energy use and monitoring the effects on tau accumulation, inflammation, and neuronal health, the team will test whether restoring healthy metabolism in these cells can slow the spread of tau and protect the brain. By mapping how the NPP pathway connects tau toxicity to microglial dysfunction, Drs. Bloom and Norambuena aim to uncover a new cellular mechanism driving AD. This knowledge could ultimately reveal early biomarkers of tau-driven metabolic stress and identify novel therapeutic targets to slow or prevent disease progression.
