To characterize how progranulin (PGRN) reduction affects tau pathology and tau-dependent phenotypes in tau transgenic mice with either PGRN haploinsufficiency or complete absence.

PGRN is a secreted glycoprotein produced by neurons and microglia encoded by the GRN gene and implicated in Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Reduced PGRN levels caused by a GRN variant are linked to increased AD risk. While the GRN AD risk variant has no effect on amyloid beta levels, it is associated with increased cerebrospinal fluid tau levels in the human Alzheimer’s Disease Neuroimaging Initiative dataset. This suggests that PGRN reduction may exacerbate tau pathology and subsequently increase AD risk.

PS19 mice overexpressing human 1N4R tau protein with the P301S mutation were crossed with Grn-/- mice to generate 6 different genotypes: wild type (WT), Grn+/-, Grn-/-, PS19, PS19 Grn+/-, and PS19 Grn-/-. Immunohistochemistry was performed on the hippocampus of harvested mouse brains from each genotype to detect PGRN and microglial marker Iba1. Body weights of the mice were tracked biweekly, and behavior patterns were observed in an elevated plus maze test.

The PS19 mice demonstrated increased microgliosis and elevated PGRN levels compared to WT mice. PGRN levels in microglia were increased in PS19 mice compared to WT mice, however, microgliosis in PS19 mice was unaffected by PGRN deficiency.

PS19 Grn-/- mice exhibited significant body weight reduction compared to that of other genotypes, along with increased mortality rates at 10 months of age compared to WT mice. PS19 Grn-/- mice also demonstrate exacerbated disinhibition compared with Grn-/- and PS19 mice in the elevated plus maze test.

PGRN reduction modified different phenotypes of PS19 mice. This study suggests novel contributions of PGRN to AD and FTD pathology.