APP family member dimeric complexes are formed predominantly in synaptic compartments.

BACKGROUND: The amyloid precursor protein (APP), a key player in Alzheimer's disease (AD), is part of a larger gene family, including the APP like proteins APLP1 and APLP2. They share similar structures, form homo- and heterotypic dimers and exhibit overlapping functions. RESULTS: We investigated complex formation of the APP family members via two inducible dimerization systems, the FKBP-rapamycin based dimerization as well as cysteine induced dimerization, combined with co-immunoprecipitations and Blue Native (BN) gel analyses. Within the APP family, APLP1 shows the highest degree of dimerization and high molecular weight (HMW) complex formation. Interestingly, only about 20% of APP is dimerized in cultured cells whereas up to 50% of APP is dimerized in mouse brains, independent of age and splice forms. Furthermore, we could show that dimerized APP originates mostly from neurons and is enriched in synaptosomes. Finally, BN gel analysis of human cortex samples shows a significant decrease of APP dimers in AD patients compared to controls. CONCLUSIONS: Together, we suggest that loss of full-length APP dimers might correlate with loss of synapses in the process of AD.

The Influence of Distinct Regulatory miRNAs of the p15/p16/RB1/E2F Pathway on the Clinical Progression of Glioblastoma Multiforme.

OBJECTIVE: The microRNAs (miRNAs) -26a, -24, and -21 have been reported as regulators of the P15/P16/RB1/E2F pathway, which plays a major role in glioblastoma multiforme (GBM) progression. In the present study, their predictive marker for the progression of GBMs is evaluated and described. METHODS: The expression of miRNA-21, -24, and -26a was analyzed as fold change (FC) in tumor specimens of 104 patients with GBM and 8 specimen of non-neoplastic brain tissue as control group. The results were referred to the individual clinical data sets and evaluated statistically. RESULTS: The FC of miRNA-21, -24, and -26a was 1.51 ± 1.35, 0.75 ± 0.67, and 0.39 ± 0.24 in the tumor samples. Within the control group, FC of miRNA-21, -24, and -26a was 0.31 ± 0.51, 0.66 ± 0.33, and 0.18 ± 0.11, respectively. MiRNA-26a and -21 were significantly overexpressed in GBM samples compared with healthy brain tissue (miRNA-21: P < 0.001; miRNA-26a: P = 0.011). High expression ofmiRNA-24 trended for a prolonged overall survival (P = 0.07). Patients with high miRNA-26a expression showed a significantly prolonged progression-free survival (hazard ratio 0.21; 95% confidence interval 0.09-0.51], P < 0.001) and overall survival (hazard ratio 0.3; 95% confidence interval 0.136-0.682], P = 0.003). The effect of miRNA-26a was mediated via regulation of mRNA of RB1. There was a significant inverse correlation between mRNA-26a and mRNA expression of RB1. CONCLUSIONS: The expression levels of miRNA-26a and -24 turned out to be promising predictors of further clinical course in patients with GBM multiforme.