Amyloid buildup in the brain begins many years before the cognitive symptoms of Alzheimer’s disease (AD) become apparent. This accumulation is followed by the spread of pathological tau and subsequent neuronal cell death. While it is well established that amyloid and tau pathologies disrupt protein production and impair many normal cell functions, the precise relationships between these changes and cognitive decline remain unclear. However, it is known that the loss of normal cognitive functions correlates with the spread of tau tangles from the hippocampus and with the degree to which synapses—the connections between neurons—are lost in the brain.
The synaptic connections among neurons are the fundamental unit of intricate networks that transmit information throughout the brain and across brain regions. The coordinated electrical signaling within these networks is essential for memory, thinking, and cognitive functions. When neurons or synapses are damaged or lost, these communication pathways break down, making it harder for the brain to process information. As a result, cognitive abilities decline. The health of brain networks is often assessed by functional MRI (fMRI). In AD patients, fMRI studies show consistent deficits in specific vulnerable brain networks, most notably in the Default Mode Network (DMN), which becomes overloaded with amyloid early in the disease. fMRI imaging shows an initial increase in activity followed by a crash of normal communication functions. Previous work from the Busche and Harris labs, as well as others, shows that in mouse models, amyloid increases the electrical activity of some neurons—causing them to send out more signals than appropriate—while pathological tau suppresses this activity. In a mouse model where both amyloid and tau are present, Drs. Busche and Harris found tau’s suppressive effect is stronger. The field is just starting to address how changes in individual cell function due to AD pathology translate into disruptions of the larger brain networks of which they are a part. Recent technological advances now allow researchers to measure single neuron activity and large-scale network activity simultaneously, providing the researchers with the tools necessary to address how cellular changes impact larger brain networks. In this study, Drs. Busche and Harris are exploring how tau and amyloid change the electrical activity of individual neurons and how these changes relate to the function of large brain networks, like the DMN, that support cognition.
The team is pursuing two experimental aims. In the first aim, they are investigating whether amyloid- and/or tau-related deficits in communication between brain regions are linked to changes in the activity of individual neurons. They are using an imaging technique similar to fMRI called focused UltraSound (fUS) to record DMN function in mice. These mice also have electrical probes implanted in their brains to simultaneously measure neuronal activity in the regions forming the DMN. The team is collecting data from amyloid and tau mouse models at two ages (young and old) to determine if the activity changes as the disease progresses. In the second aim, they are exploring which genes or proteins may predict the loss of normal communication in vulnerable brain networks like the DMN. To do this, they are measuring gene expression (spatial transcriptomics) in brain samples from the same mice used in aim one. These integrated analyses should shed light on how cell-level changes impact cognition.
At the close of the first year of funding, the team has made significant progress toward their experimental aims. For Aim 1, the researchers built on their preliminary findings by investigating how amyloid and tau alter the activity of individual neurons (versus groups of neurons). Using two amyloid mouse models (APP/PS1 and APP-NLGF) and two tau mouse models (rTg4510 and PS19), they demonstrated that amyloid pathology drives excessive neuronal firing at the single-cell level, while tau pathology disrupts normal firing patterns. In a mouse model expressing both amyloid and tau, the combined effect exacerbated neuronal dysfunction, leading to widespread impairments in brain information processing. These findings are significant for two reasons. First, they help clarify the critical molecular processes that cause brain activity to falter early in AD. Second, they reinforce the importance of pursuing treatments that target both amyloid and tau rather than focusing on either one alone. Additionally, the team identified and characterized the specific form of tau responsible for suppressing neuronal activity and found that this suppression is associated with disrupted brain network rhythms and weakened communication between the hippocampus and the cortex, two regions critical for memory and information processing. In Aim 2, they successfully established the groundwork for their second year. Moving forward, they will employ advanced transcriptomic methods to pinpoint how amyloid and tau alter gene expression within neurons and glial cells.
