Does loss of interaction of progranulin and prosaposin promote neurofibrillary tangle development?

Abstract

AbstractBackgroundProgranulin (PGRN) and prosaposin (PSAP) have lysosomal and neurotrophic properties. Reduced amounts of PGRN in mutant tau‐expressing Alzheimer’s disease (AD) model mice exacerbated phosphorylated tau pathology. The implication of PGRN in tangle formation in AD is not understood nor the association of PSAP with AD. Both features need further research.MethodFixed human brain tissue sections of middle temporal gyrus (MTG) from low plaque (LP)(n=4), high plaque (HP)(n=4) non‐demented (ND), and AD (n=4) cases, and superior frontal gyrus from a presenilin‐1 mutated case and frontal temporal lobar degeneration (FTLD) cases (n=3) with heterozygous granulin mutations were employed in this study. The interaction of PGRN and PSAP was identified with proximity ligation assay (PLA). The colocalization of PGRN and PSAP with tangle was identified by fluorescent immunohistochemistry and triple‐color confocal microscopy with antibodies to phosphorylated tau (p‐tau). PGRN and PSAP fluorescence intensity was measured in p‐tau positive neurons and compared to adjacent p‐tau negative neurons.ResultDifferent p‐tau positive structures were measured and related to the levels of PGRN and PSAP. Extracellular neuropil threads appeared to have no association with these proteins. Reduced levels of PGRN and PSAP were detected in p‐tau positive neurons compared to control neurons in all groups. Average levels of PGRN in control neurons were decreased as disease developed. In the AD group, reduced signals of these proteins were observed overall in neurons without p‐tau, and absent in fully matured neurofibrillary tangles. The levels of PGRN and PSAP negatively correlated with p‐tau immunoreactivity. The presenilin‐1 mutated case with numerous tangles in frontal cortex had absence of PGRN and PSAP in tangles, but colocalization of PGRN and PSAP was evident in adjacent neurons. FTLD cases showed absence of PGRN in most neurons, but continued expression of PSAP. The interaction of PGRN and PSAP in neurons was verified with a PLA assay.ConclusionP‐tau positive neurons had significantly less PGRN and PSAP even in the non‐demented groups, which suggests this could be an early event of tangle formation. The insufficiency of both PGRN and PSAP in neurons might lead to accumulation of p‐tau protein due to deficits in lysosomal activity.