Benskey Lab

Alzheimer’s disease (AD) and related dementias (ADRDs) are characterized by progressive memory loss, cognitive decline, and behavioral changes. Healthy brain function depends on effective communication between synapses, and mounting evidence indicates synapse loss is a primary driver of cognitive impairment in AD/ADRDs and other neurodegenerative disorders. Thus, preserving functional synapses represents a critical therapeutic goal.

Synapses are constantly remodeled through a balance of synaptic formation and removal. The removal of synapses, known as synaptic pruning, is essential for normal neuronal communication and plasticity. In the brain, pruning is largely controlled by the complement system, a group of immune proteins that tag weak or damaged synapses for clearance by microglia (the brain’s immune cells). Under normal conditions, this process is tightly regulated. However, the complement system is overactivated in AD/ADRDs, and this leads to excessive complement synaptic pruning and impaired cognitive function.

Our lab focuses on understanding how and why complement synaptic pruning becomes dysregulated in these diseases. Specifically, we aim to identify the molecular mechanisms that allow the complement system to differentiate between synapses that should be removed and those that should be preserved. We have discovered synaptic molecules that inhibit complement activation and are exploring how these might be used to develop new therapies that protect synapses from degeneration. We are also investigating how key features of Alzheimer’s pathology—particularly tauopathy—trigger complement activation and promote synaptic pruning.

By uncovering the mechanisms that control complement-mediated synaptic pruning, the Benskey Lab aims to develop new, disease-modifying strategies to preserve synapses and maintain cognitive function in AD/ADRDs.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by accumulation of misfolded forms of the protein alpha-synuclein—which forms aggregates known as Lewy bodies—and the degeneration of specific populations of neurons. While the precise cause of PD remains unknown, growing evidence suggests neuroinflammation plays a central role in driving disease progression.
Neuroinflammation is the brain’s immune response to injury or disease and involves the coordinated activity of glia (microglia and astrocytes) and numerous immune signaling pathways. Notably, inflammation is present throughout the brain and body in individuals that develop PD, often decades before the appearance of motor symptoms. This pattern suggests an early immune trigger may initiate a chronic inflammatory response that contributes to- or causes neurodegeneration.

The Benskey Lab aims to understand what drives this inflammatory response and how it leads to neuronal loss in PD. We have identified the complement system, which is a network of immune proteins, as an early responder to PD-related pathology. Our research shows that reactive glia dramatically increase the expression of complement proteins in response to misfolded alpha-synuclein, and that misfolded alpha synuclein can directly activate the complement system. Importantly, this activation occurs prior to neurodegeneration, suggesting the complement system may represent an early-stage immune mediator that initiates or amplifies neuroinflammation in PD.

Ongoing studies in the Benskey Lab are focused on uncovering the molecular mechanisms that drive complement activation, determining whether complement proteins directly target neurons containing Lewy bodies, and testing whether complement inhibition can protect neurons and slow disease progression.

By investigating how neuroinflammation and the complement system responds to early-stage PD pathology, the Benskey Lab seeks to identify strategic points suitable for therapeutic intervention aimed at dampening inflammation and preventing degeneration.