All of these observations suggest that deficient expression of PGRN triggered by elevated expression of TMEM106B promotes neurodegeneration. However, in contrast to FLTD TDP brains with reference 2 GRN mutations, we found that TMEM106B mRNA and protein levels are reduced in AD brains. In the present study, the frequency of T185 and S185 isoforms was not significantly different between AD and non AD cases. As a result, we unexpectedly found a reverse inverse correlation between TMEM106B and PGRN in AD brains at least at mRNA expression levels. The possible scenario that TMEM106B plays a protective role against Inhibitors,Modulators,Libraries the neurodegen erative processes in AD could therefore be raised, although further studies on in vitro and in vivo TEME106B knock down models are required to evaluate this possibility.

In the present study, AD cases showed significantly elevated mRNA levels of PGRN, when compared with Inhibitors,Modulators,Libraries the levels in non AD cases. However, we did not find a significant elevation of PGRN protein levels in AD brains, leading to no obvious inverse correlation between TMEM106B and PGRN protein expression levels. The inconsistency between PGRN mRNA and protein levels is attributable to the complex post transcriptional modifi cation of the PGRN protein. The PGRN protein contains 7. 5 tandem repeats of 12 cysteinyl motifs separated by linkers. When secreted extracellularly, PGRN cleaved by elastase and matrix metalloproteases Inhibitors,Modulators,Libraries within linker regions generates several smaller fragments called granulins, composed of GRN A to G and para granulin or epithelins.

Importantly, the full length PRGN and its cleaved fragment GRNs play a discrete role in regulation of various biological responses. PGRN exhibits neurotrophic and anti inflammatory activities, whereas GRNs serve as a proinflammatory mediator. Inhibitors,Modulators,Libraries Expression levels of PGRN, whose release is facilitated by anti inflammatory stimuli in microglia, are elevated in multiple sclerosis brains. Astrocytes produce large amounts of secretory leukocyte protease inhibitor, a negative regulator of proteolytic processing of PGRN, in response to proinflammatory stimuli. In contrast, PGRN acts as a chemotactic factor for microglia Inhibitors,Modulators,Libraries capable of producing large amounts of reactive oxygen species, although microglia, following exposure to PGRN, show an enhanced capacity to phago cytose amyloid B1 42. At present, therefore, whether upregulated expression of PGRN in AD brains plays a neuroprotective or neurotoxic role remains unknown. We found that overexpression of either TMEM106B or PGRN transgene in SK N SH neuroblastoma cells does not immediately affect endogenous levels e-book of PGRN or TMEM106B mRNA, excluding the direct interaction between both in transcription regulation of mutual genes.