AD cases showed signifi cantly reduced levels of TMEM106B, when compared with the levels in non AD cases. AD cases HTC showed a trend for elevated ex pression levels of PRGN when compared with the levels in non AD cases, but the difference did not reach statistical significance. We found no dis cernible correlation between TMEM106B and PRGN protein expression levels. Immunohistochemical analysis of TMEM106B expression in Alzheimers disease and non Alzheimers disease brains We next studied the expression of TMEM106B in the frontal cortex and the hippocampus of six AD cases and 13 non AD cases, composed of four NC cases, four ALS cases, three PD cases, and two MSA cases, presented in Table 1, by immunohistochemistry using the A303 439A antibody. Before starting this, we investigated TDP 43 path ology in the brains examined.

Among 19 cases, four AD cases and three ALS cases but no cases of NC, PD, or MSA showed neuronal or glial pTDP 43 immunoreac tivity in Inhibitors,Modulators,Libraries the frontal cortex and or the hippocampus. In all cases examined, TMEM106B was expressed in the majority of cortical neu Inhibitors,Modulators,Libraries rons, hippocampal pyramidal neurons and dentate gyrus granule cells, located in the cytoplasm by forming fine granular structures, particularly enriched in the soma and in proximal neurites. TMEM106B immu noreactivity was occasionally concentrated in the peri nuclear region by forming small nodular structures in some populations of hippocampal pyramidal neurons. Furthermore, subpopulations of oligodendrocytes, reactive astrocytes, and microglia expressed TMEM106B intensely, located in the cytoplasm.

Neuronal cytoplasmic TMEM106B im munoreactivity was greatly reduced after absorption of the antibody by extract of the Xpress tagged TMEM106B pro tein. In AD brains, cortical neurons and hippocampal pyram idal neurons were Inhibitors,Modulators,Libraries greatly reduced in number, along with substantial Inhibitors,Modulators,Libraries reduction of Inhibitors,Modulators,Libraries TMEM106B expressing neurons. However, surviving neurons in AD brains moderately or intensely expressed TMEM106B immunoreactivity in the cytoplasm. Senile plaques were most often unlabeled and rarely faintly labeled by the A303 439A anti body. In contrast, senile plaques, neurofibril lary tangles, and the perivascular neuropil were frequently and intensely labeled with anti PGRN antibody EPR3781. Some populations of activated microglia also expressed PGRN.

The vacuoles of granulovacuolar degeneration often found in pyramidal neurons of the hippocampal CA1 region were devoid of TMEM106B immunoreactivity. Overexpression of TMEM106B and PGRN did not alter their mRNA expression levels Finally, we studied ROCK1 by qPCR the direct inverse relationship between TMEM106B and PGRN mRNA expression in SK N SH neuroblastoma cells following overexpression of Xpress tagged TMEM106B, PGRN, and LacZ proteins. Transient overexpression of the TMEM106B, PGRN, or LacZ transgene did not significantly alter the levels of en dogenous TMEM106B and PGRN mRNAs.