Progranulin (PGRN) is a protein encoded by the GRN gene with multiple identified 
functions including as a neurotrophic factor, tumorigenic growth factor, 
anti-inflammatory cytokine and regulator of lysosomal function. A single 
mutation in the human GRN gene resulting in reduced PGRN expression causes types 
of frontotemporal lobar degeneration resulting in frontotemporal dementia. 
Prosaposin (PSAP) is also a multifunctional neuroprotective secreted protein and 
regulator of lysosomal function. Interactions of PGRN and PSAP affect their 
functional properties. Their roles in Alzheimer's disease (AD), the leading 
cause of dementia, have not been defined. In this report, we examined in detail 
the cellular expression of PGRN in middle temporal gyrus samples of a series of 
human brain cases (n = 45) staged for increasing plaque pathology. 
Immunohistochemistry showed PGRN expression in cortical neurons, microglia, 
cerebral vessels and amyloid beta (Aβ) plaques, while PSAP expression was mainly 
detected in neurons and Aβ plaques, and to a limited extent in astrocytes. We 
showed that there were increased levels of PGRN protein in AD cases and 
corresponding increased levels of PSAP. Levels of PGRN and PSAP protein 
positively correlated with amyloid beta (Aβ), with PGRN levels correlating with 
phosphorylated tau (serine 205) levels in these samples. Although PGRN 
colocalized with lysosomal-associated membrane protein-1 in neurons, most PGRN 
associated with Aβ plaques did not. Aβ plaques with PGRN and PSAP deposits were 
identified in the low plaque non-demented cases suggesting this was an early 
event in plaque formation. We did not observe PGRN-positive neurofibrillary 
tangles. Co-immunoprecipitation studies of PGRN from brain samples identified 
only PSAP associated with PGRN, not sortilin or other known PGRN-binding 
proteins, under conditions used. Most PGRN associated with Aβ plaques were 
immunoreactive for PSAP showing a high degree of colocalization of these 
proteins that did not change between disease groups. As PGRN supplementation has 
been considered as a therapeutic approach for AD, the possible involvement of 
PGRN and PSAP interactions in AD pathology needs to be further considered.