The synapse is the fundamental unit of the nervous system, enabling communication between brain cells and providing a substrate for experience-dependent plasticity to drive adaptive behaviors. Altering the strength of synapses between specific cells or neuronal ensembles is thought to underlie higher brain functions such as learning and memory, whereas synaptic degradation is observed in many neurological pathologies, such as Alzheimer's disease (AD) and related dementias. Despite the clear significance of synaptic communication, the relationship between impaired synaptic function, progression of AD symptoms, and cognitive decline remains unclear. However, recent breakthroughs in molecular microscopy enable direct imaging of the progression of pathological synaptic deficits in mouse models of Alzheimer's disease. Our approach is to fluorescently tag synaptic proteins and AD markers to track them throughout disease progression using in vivo two-photon microscopy. By imaging large populations of synapses comprising entire cortical and hippocampal circuits, we strive to gain a detailed understanding of how molecular pathologies affect synaptic physiology and ultimately give rise to cognitive decline. This approach will yield a detailed time course of the progression of synaptic and cognitive Alzheimer's pathologies that may reveal effective treatment windows and novel avenues for therapeutic interventions for human disease.
This proposal will harness novel tools in genetics and microscopy to study Alzheimer's disease at the molecular level in a rodent model, with a particular focus on understanding initiating factors of disease. We will fluorescently label disease biomarkers that are also present in the humans, install windows in the skulls of living mice to image how these disease markers spread in the brain, and use behavioral testing to correlate the observed pathogenesis with progressive memory deficits throughout the development of Alzheimer's. Together, these longitudinal imaging and behavioral data will give us an incredibly detailed molecular view of how Alzheimer's spreads throughout entire brain regions and how it causes memory loss, potentially highlighting novel biological signals to detect disease in humans.
