A recent study found that the frequency of the protective C allele on rs1990622 in the TMEM106B gene, show ing the complete linkage disequilibrium with p. T185S on rs3173615, is reduced in AD cases exhibiting TDP 43 pathology. In contrast, we found no difference in the frequency of T185 and S185 isoforms on rs3173615 between AD and non AD cases. TDP 43, a nuclear RNA DNA binding protein selleck capable of interacting with UG TG repeat stretches of target RNAs DNAs, plays a key role in regulation of transcription, alternative splicing, mRNA sta bility and transport, and microRNA biogenesis, actively involved in the pathogenesis of FTLD ALS termed TDP 43 proteinopathy. Because TMEM106B is identified as a direct target for TDP 43 regulated gene expression, the cytoplasmic sequestration of TDP 43 in TDP 43 proteinopathy might induce deregulated expression of TMEM106B Inhibitors,Modulators,Libraries in neurons containing TDP 43 positive inclusions.

In the present study, four out of six AD cases showed TDP 43 pathology in the frontal cortex and or the hippocampus. Among these we found that three cases show markedly re duced TMEM106B mRNA and protein expression levels, suggesting an involvement of aber rant regulation of the TMEM106B gene by TDP 43 in the pathogenesis of AD, although Inhibitors,Modulators,Libraries larger cohorts are re quired to evaluate this possibility. In contrast to downregulation of TMEM106B expres sion, the expression of two paralogues of TMEM106B was markedly upregulated at mRNA levels, almost specifically expressed in AD brains. The corresponding genes are located in different chro mosomes that is, TMEM106A, TMEM106B, and TMEM106C whose expression is presumably regulated by distinct mechanisms.

The pos sibility exists that upregulation of the functionally relevant paralogues reflects a compensation Inhibitors,Modulators,Libraries for a deficiency of TMEM106B in AD brains. Further studies Inhibitors,Modulators,Libraries are required to evaluate this possibility. In AD brains, granulovaculoar degeneration bodies, a kind of autophagosome, express immunoreactivity for charged multivesicular body protein 2B, whose genetic mutations definitely cause FTLD. We found that granulovacuolar degeneration vacuoles located in hippocampal CA1 pyramidal neurons of AD brains are devoid of TMEM106B immunoreacitivity. At present, the mechanisms responsible for reduced expression of TMEM106B in AD brains remain unknown.

If downregu lation of TMEM106B is directly or indirectly involved in neurodegeneration, we could propose the hypothesis that TMEM106B plays a protective role against the neurodegen erative processes Inhibitors,Modulators,Libraries in AD. Worthy of note is that by analyzing the promoter region of the TMEM106B gene with bioinfor matics tools for the Database of Transcriptional Start Site and the Matrix Search for Transcription Factor Binding Sites, we identified three potential binding sites for POU class 2 homeobox 1, a transcription factor of the POU transcription factor family whose SNP is closely associated with the genetic more risk of AD.