Role of Secreted Protein Acidic and Rich in Cysteine (SPARC) in Immunometabolic Control of Age-Related Inflammation

2020

Inflammation associated with aging is an important trigger for Alzheimer’s disease (AD) development. There is growing evidence that age-related inflammation mediated via the activation of the NLRP3 inflammasome is an important mechanism for loss of cognition and memory, and development of AD. Studies from our lab have identified that the NLRP3 inflammasome controls the development of inflammation-associated degenerative diseases during aging. Consistent with our data, independent studies also have demonstrated increased activation of the NLRP3 inflammasome in AD in humans, and that genetic loss of NLRP3 protects against dementia in the amyloid precursor protein/PS1 mouse model of AD. This proposal is based on our findings that 14% caloric restriction, or CR (from the CALERIE-II study) in healthy humans lowers a matricellular protein called SPARC. To determine whether SPARC is a driver of CR’s salutary effects on reducing inflammation, we pursued this protein to understand its function in macrophages, the major cell type that is a source of inflammatory cytokines in aging. SPARC is a 32kDa calcium-binding matricellular protein. To determine whether reduction in SPARC as caused by CR lowers inflammation, we have created microglia and tissue resident macrophage-specific SPARC-deficient mice. Given our preliminary data that SPARC can control inflammation, we hypothesize that downregulation of SPARC in tissue resident macrophages and microglia will protect against inflammasome activation, age-related astrogliosis, and loss of memory and cognition.


Funding to Date

$172,500

Focus

Immune System Structures, Translational

Researchers

Vishwa Deep Dixit, D.V.M., Ph.D.