Gordon Lab

Cellular Senescence

The risk of developing Alzheimer’s disease (AD) increases over the lifespan, with one in two Americans showing symptoms after the age of 85. An important premise of geroscience is that modulating the aging process will have pleiotropic effects on multiple organ systems, producing widespread reductions in morbidity and decreasing pathology associated with many co-morbid conditions simultaneously. Calorie restriction and rapamycin treatment are two approaches shown to slow the rate of biological aging, resulting in enhanced healthspan and prolonged lifespan. Aging is associated with the appearance of senescent cells. While it was originally believed that a nondividing condition resulted in senescent cells with reduced functionality, it is increasingly recognized that senescent cells undergo many physiological changes, leading to the production and secretion of a complex mixture of cytokines, signaling molecules and matrix metalloproteinases that can affect function of nonsenescent cells. Selective removal of senescent cells is generally associated with improved healthspan in aged mice and reduction in several phenotypes in age-related disease. My lab is poised for comprehensive examination of cellular senescence in brain during aging and Alzheimer’s disease. We will determine whether two well-characterized methods to slow the rate of biological aging (calorie restriction and rapamycin treatment) will mitigate age-dependent tauopathy, neurodegeneration and senescent cell accumulation. Pharmacological and genetic methods to deplete senescent cells will determine whether this can delay the tauopathy phenotype in this model. Taken together, these experiments will determine whether age-dependent tauopathy can be mitigated by treatments affecting longevity. 

Innate Immune Activation  

Inflammation plays an important role in Alzheimer’s disease. Local activation of microglia and astrocytes release cytokines which can influence amyloid and tau pathology. Because global inhibition of systemic inflammation using steroidal or non-steroidal anti-inflammatory drugs has not proven effective in clinical trials, the molecular mechanisms linking neuroinflammation and tauopathy are likely to be more complex than previously suspected, requiring more sophisticated and selective therapies than have been attempted to date. 

This project will identify the most relevant anti-inflammatory strategies impacting tau using molecular therapeutics. Assuming that tauopathy contributes to cognitive decline, and that slowing the development of tau deposits will slow the rate cognitive decline, approaches to reduce CNS inflammation may be useful interventions in individuals that already have symptoms of Alzheimer’s disease and other tauopathies. This project uses adeno-associated viral vector mediated gene delivery of molecular therapeutics to inactivate select pro-inflammatory proteins or to activate anti-inflammatory proteins in the brain of two transgenic mouse models with tauopathy. We monitor the effects of the molecular therapeutics at the behavioral and neuropathological levels. Taken together, these results will provide preclinical evidence supporting one or more of these approaches to move forward into clinical testing in Alzheimer’s disease and/or other tauopathies.

Transgenic Mice

Transgenic mice are important model systems for exploring disease etiology and treatments.  New models affecting the brain require functional assessment. Consequently, a suite of mouse behavioral hardware and software has been established for this purpose. Using various chambers and mazes, mice can be tested for sensory and motor function, locomotor activity, social interaction and aggression, neophobia, anxiety, learning and memory. These tests allow critical insight into how gene expression changes translate into behavioral and cognitive outcomes.