Alzheimer’s disease (AD) gradually erodes the brain’s communication networks, leading to memory loss, confusion, and cognitive decline. While scientists have long focused on the buildup of amyloid and tau proteins as key drivers of this process, it has become clear that AD also disrupts how neurons interact and maintain balance across the brain’s circuits. Like electrical circuits in a home, brain circuits are pathways of connected neurons that produce specific outcomes like a thought, behavior, or emotion. At the core of this disruption is an imbalance between two major types of neurons: excitatory neurons, which activate other nerve cells, and inhibitory neurons, which help keep that activity in check. When this balance is lost, such as when excitatory neurons fire too much or inhibitory neurons fail to regulate them, the brain’s signaling becomes unstable, contributing to the confusion and dysfunction seen in AD. Recent research shows that inhibitory neurons may be particularly vulnerable to tau accumulation. Inhibitory neuron loss can lead to hyperactive signaling, seizures, and accelerated neurodegeneration. Yet, it remains unclear why these inhibitory neurons are selectively affected and what mechanisms cause their dysfunction.
Dr. Ikezu and his team are exploring one promising explanation for how brain circuits become overactive in AD: tiny cellular messengers called extracellular vesicles (EVs) help spread toxic molecules between cells, disrupting the brain’s delicate balance between excitation and inhibition. EVs are small, membrane-bound packets released by neurons and glia that carry proteins, fats, and genetic material used for cell-to-cell communication. In AD, Dr. Ikezu’s group and others have found that these vesicles can transport harmful, phosphorylated forms of tau to healthy cells, essentially spreading damage from one part of the brain to another. His team has isolated EVs from both postmortem human brain tissue and amyloid mice and found that these brain-derived EVs carry not only abnormal tau, but also other molecules that alter neuronal activity and promote inflammation. When healthy neurons were exposed to these tau-containing EVs, they showed electrical changes consistent with hyperactivity, suggesting that EVs can directly disturb the brain’s excitatory/inhibitory balance. Further experiments revealed that inhibitory neurons were especially vulnerable; they lost key synaptic proteins that help control firing rates and stabilize network activity. Importantly, EVs from Alzheimer’s brain tissue were enriched with proteins involved in GABA-receptor signaling, the main pathway that enables inhibitory communication, suggesting a specific link between tau-carrying EVs and the weakening of inhibitory circuits. Building on these findings, Dr. Ikezu and his colleagues hypothesize that EVs containing pathogenic tau selectively impair GABAergic inhibitory signaling, driving hyperactivity, inflammation, and ultimately neurodegeneration in Alzheimer’s disease.
They will test this hypothesis through two complementary aims. First, they will identify which molecules allow EVs to interact with neurons in healthy, amyloid (APP), and tau (PS19) mouse models. Using a cutting-edge labeling technique called TurboID, they can “tag” and track the proteins that come into direct contact with EVs in the brain. This will help pinpoint which proteins enable EVs carrying toxic tau to attach to and enter inhibitory neurons and disrupt GABAergic inhibitory signaling. In the second aim, the researchers will explore how these interactions change intercellular communications of excitatory and inhibitory neurons. They will expose human induced pluripotent stem cell-derived neurons to AD brain-derived EVs and use electrophysiology and multi-electrode array recordings to measure how neuronal signaling and network activity shift in response.
