Gordon Lab

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. Furthermore, new techniques such as single cell RNA sequencing are defining distinct microglial subtypes based on gene expression patterns, including homeostatic, disease associated, interferon response, and other subtypes of microglia in aging and AD. Major projects in the lab seek to elucidate the molecular mechanisms by which these microglial subtypes contribute to the formation and perpetuation of Alzheimer pathology.

Using pharmacologic and genetic tools, we are performing experiments to manipulate numbers and phenotypes of select microglial subtypes to explore how this contributes to Alzheimer-like pathology, cognitive impairment and neurodegeneration in mouse models with funding from the Rotary International Coins for Alzheimer Research Trust. Other projects use adeno-associated viral vector mediated gene delivery of molecular therapeutics that may ultimately prove useful treatments for Alzheimer’s disease and related dementias.

Age, female sex and genetically inheriting a variant of the apolipoprotein E gene (the ApoE-ε4 allele) are the largest risk factors for developing Alzheimer’s disease and related dementias. A major focus of the lab is discovering how these variables accelerate neuropathology, cognitive impairment and neurodegeneration using mouse models. We have examined whether two well-characterized methods to slow the rate of biological aging (calorie restriction and rapamycin treatment) can mitigate age-dependent tauopathy, neurodegeneration and senescent cell accumulation. We are using genetic tools to explore how microglial phenotypes are changed by the presence of the ApoE-ε4 allele and whether this is necessary and sufficient to result in cognitive impairment and neurodegeneration. Studies are conducted in both male and female mice to explore sex differences. Experiments to manipulate reproductive aging leading to loss of estrogens mimicking menopause will be explored to determine how this impacts the time course of Alzheimer-like progression in these mouse models. Taken together, these experiments will help to elucidate molecular mechanisms underlying these risk factors and may suggest therapeutic strategies for minimizing their impact.

Current Funding

• Rotary International Coins for Alzheimer’s Research Trust; Role of Microglial Cellular Senescence in a Mouse Model With Amyloid-Induced Tauopathy; 2024-2026.
  
  
• Michigan State University College of Human Medicine and Department of Translational Neuroscience 25-DFI-I-0000000530; Gene Expression Changes Accompanying Replicative Senescence in Microglia; 2024-2026.

Past Funding

• Henry Ford Health System; Enhancing the therapeutic gain of radiation therapy for brain cancer by reducing cellular senescence; 2022-2024.
  
  
• National Institute on Aging R01AG062217; Geroscience approaches to mitigate tauopathy in aged mouse brain; 2018-2024.
  
  
• National Institute on Aging 1R41AG058283; Study of the New HDAC6i SW-100 as a Treatment for Alzheimer’s Disease and Other Tauopathies; 2017-2018.
  
  
• Alzheimer’s Association and the Judy Fund Zenith Award ZEN-15-321311; Molecular therapeutics to mitigate inflammation, tauopathy and degeneration; 2015-2018.