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

2020, 2022

2022

SPARC, secreted protein acidic and rich in cysteine, is a 32kDa calcium-binding matricellular protein. The matricellular proteins (thrombospondin-1, tenascin-C and SPARC) are extracellular matrix proteins that antagonize cell adhesions when presented to cells as soluble molecules. There is growing evidence that age-related inflammation mediated via the activation of NLRP3 inflammasome in microglia is an important mechanism in the loss of cognition and memory and the development of Alzheimer’s disease. The inflammasome is a high molecular weight protein complex that assembles in the cytosol of microglia and myeloid-lineage cells upon encounter with “damage-associated molecular patterns,” such as amyloids, lipotoxic fatty acids or extracellular ATP derived from necrotic cells. Given our data that SPARC is reduced in CR, and that increased SPARC levels can induce inflammasome activation and inflammation, we hypothesize that downregulation of SPARC in microglia will protect against inflammasome activation, age-related astrogliosis, and loss of memory and cognition.

The second year of funding will analyze the impact of SPARC knockdown in microglial cells on central nervous system inflammation and memory responses.

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

$345,000

Focus

Studies of Innate Immune Pathology, Translational

Researchers

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