Alzheimer’s disease (AD) is a multifactorial brain disorder involving the disruption of many complex mechanisms. Studying where these disrupted mechanisms intersect is becoming an intriguing area of focus. One of these intersections is the brain extracellular matrix (ECM), which provides structural support around cells, maintains their connections and stability, and supplies the infrastructure for processes occurring outside the cell, such as effective debris clearance. Research on how the brain’s ECM changes with age and AD has been limited, but Dr. Castellano and his team have made novel discoveries about the role of enzymes that regulate the ECM in AD.
The ECM is maintained through a delicate balance among several enzymes, including matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs). Recent studies have found that youth-associated proteins linked to healthy function of the brain’s ECM regulate AD pathology and brain immune cell function, raising the possibility that age-related factors can affect the disease process through the ECM. Dr. Castellano found that TIMP2 levels in the brain decline with age, interfering with the function of proteins like MMP2 in breaking down the ECM and potentially leading to accumulation of debris. This ECM disruption affects how brain cells send and receive signals, which may contribute to the cognitive decline seen in AD.
Dr. Castellano hypothesizes that mechanisms disrupting brain ECM balance influence the accumulation of Alzheimer’s pathology and responses of astrocytes and microglia, cells that normally remove debris like amyloid plaques. These mechanisms could be targeted to reduce dysfunctional cellular responses to the disease process. This work will comprehensively map how the brain’s ECM and its components are related to upstream AD pathology, while testing how perturbing ECM modifiers is restorative for cell-cell communication that may ultimately ameliorate Alzheimer’s pathology. The project will examine how implicated modifiers like TIMPs and MMPs, alongside other novel players, alter ECM pathology in amyloid-bearing mouse models. Both computational and mouse model approaches will be used to clarify specific mechanisms of TIMPs/MMPs. Through careful dissection of these mechanisms and additional experiments that examine translational paths targeting these modifiers, this project will address the potential of targeting key ECM regulators as a therapeutic approach.
