Developing Cell-Type-Specific Enhancer-AAV Vectors to Characterize and Restore Amyloid Beta- and Tau-Dependent Circuit and Cognitive Deficits in Humanized Alzheimer’s Mouse Models

Memory and cognition depend not only on individual brain cells but also on large groups of neurons that communicate with one another in a highly coordinated way. These networks generate rhythmic electrical patterns, often called brain waves, that help different parts of the brain stay in sync. Different rhythms emerge depending on what the brain is doing, and one type, known as gamma waves, is especially important for memory, attention, and learning. In Alzheimer’s disease (AD), gamma waves weaken and become less coordinated, and this loss closely tracks with cognitive decline. A growing body of laboratory and early clinical evidence suggests that restoring gamma rhythms may help improve brain function and reduce Alzheimer’s-related pathology.

Central to keeping these rhythms in sync are specialized brain cells called interneurons. Two key types—parvalbumin (Pvalb) and somatostatin (Sst)—act as musical conductors, helping large groups of neurons fire in synchrony. Work from the Palop lab shows that these two interneuron populations function as partners: Pvalb cells drive the rhythm, while Sst cells shape its strength. In AD, this partnership breaks down. Both cell types are reduced in number, and surviving cells show changes in gene activity as the disease progresses. This disruption weakens gamma oscillations and impairs communication across brain networks, but how amyloid and tau pathology affect this process has remained unclear.

Until recently, technical limitations made it difficult to study these cells in living brains. In collaboration with the Allen Institute, the Palop lab is using newly developed viral tools to precisely monitor and control specific interneuron populations in awake, behaving animals. These tools enable the team to track the real-time activity of Pvalb and Sst cells and to selectively turn them on or off. This approach allows the Palop team to directly observe how interneuron activity shapes brain rhythms, behavior, and learning.

The team is applying these tools to mouse models that develop amyloid or tau pathology, tracking how interneuron signaling, gamma activity, learning, and everyday behaviors change as disease-related pathology accumulates over time. Because behavioral changes can be subtle, the researchers are using advanced behavioral tracking combined with machine-learning approaches to analyze large, complex datasets. They are also examining brain activity during sleep, a critical period when gamma and other rhythms support brain health and influence the handling of Alzheimer’s pathology.

At the end of the first year of funding, the team has made substantial progress. They have developed and validated new systemic, enhancer-driven AAV tools that allow highly selective and simultaneous targeting of Pvalb and Sst interneurons. They are refining current models of gamma oscillation control and have demonstrated that Pvalb and Sst cells act synergistically to generate gamma rhythms and that even small timing delays between their activation can completely disrupt gamma activity. In parallel, studies in humanized AppNLF/APOE4 knock-in mice have revealed striking and selective vulnerability of Sst interneurons, which show reduced firing rates and impaired coupling to gamma rhythms, whereas Pvalb neurons remain relatively preserved. Additional work across multiple AD mouse models is showing that Pvalb interneurons are underactive, leading to reduced gamma power and abnormal network activity, and that restoring Pvalb activity rescues these deficits. Together, these findings strengthen the case that interneuron dysfunction is a key driver of network disruption in AD.

In the next funding period, the team will expand these efforts to define how interneuron-driven gamma activity shapes brain-wide molecular and functional outcomes. They are examining how coordinated interneuron activity drives widespread changes in gene expression across neurons and glial cells, as well as across connected brain regions. These studies position interneuron-based circuit modulation as a powerful strategy to correct both network-level dysfunction and downstream molecular changes in AD, with the goal of identifying precise cellular and timing-based targets to guide future therapeutic development.