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Amyloidogenic processing of the amyloid precursor protein (APP) results in the generation of ␤-amyloid, the main constituent of Alzheimer plaques, and the APP intracellular domain (AICD).Recently, it has been demonstrated that AICD has transactivation potential; however, the targets of AICD-dependent gene regulation and hence the physiological role of AICD remain largely unknown. We analyzed transcriptome changes during AICD-dependent gene regulation by using a human neural cell culture system inducible for expression of AICD, its coactivator FE65, or the combination of both. Induction of AICD was associated with increased expression of genes with known function in the organization and dynamics of the actin cytoskeleton, including ␣2-Actin and Transgelin (SM22). AICD target genes were also found to be differentially regulated in the frontal cortex of Alzheimer's disease patients compared with controls as well as in AICD/FE65 transiently transfected murine cortical neurons. Confocal image analysis of neural cells and cortical neurons expressing both AICD and FE65 confirmed pronounced changes in the organization of the actin cytoskeleton, including the destabilization of actin fibers and clumping of actin at the sites of cellular outgrowth. Our data point to a role of AICD in developmental and injury-related cytoskeletal dynamics in the nervous system. INTRODUCTIONThe amyloid precursor protein (APP) is a type-1 transmembrane protein composed of a large extracellular and a small intracellular domain and has been widely implicated in the pathogenesis of Alzheimer's disease (AD). APP can undergo proteolytic cleavage by ␤-and ␥-secretase activities, resulting in the production of ␤-amyloid (A␤) (Selkoe, 1994). A␤ is the main constituent of amyloid plaques and is thought to be neurotoxic by inducing oxidative stress, inflammation, and neurodegeneration (Mattson, 2004). The intraneuronal accumulation of A␤ protofibrils is thought to cause progressive neurotoxicity in cortical neurons (Hartley et al., 1999). In addition, the secretion of soluble A␤ oligomers inhibits hippocampal long-term potentiation and alters the memory of complex learned behavior (Walsh et al., 2005).The APP intracellular domain (AICD), a small 6-kDa protein, originates from APP cleavage mediated by ␥-secretase activity (Octave et al., 2000). This cleavage can occur after Val636 (AICD59), Ala638 (AICD57), or Leu645 (AICD50) corresponding to the ␥-or -cleavage site ( Figure 1A) of the ␥-secretase complex (Sastre et al., 2001;Yu et al., 2001). More recently, AICD was shown to have transactivation potential (Cao and Sudhof, 2001). AICD levels are detectable in membrane fractions of murine total brain homogenates, and they increase significantly in mice overexpressing the Swedish mutation of human APP (Ryan and Pimplikar, 2005). Moreover, Hirano bodies found in the degenerating neurons of Alzheimer's patients stain positive with antisera raised against the cytoplasmic domain of APP (Munoz et al., 1993), suggesting an accumulation of AICD during Alzheimer...

Filaminopathy is a subtype of myofibrillar myopathy caused by mutations in FLNC, the gene encoding filamin C, and histologically characterized by pathologic accumulation of several proteins within skeletal muscle fibers. With the aim to get new insights in aggregate composition, we collected aggregates and control tissue from skeletal muscle biopsies of six myofibrillar myopathy patients harboring three different FLNC mutations by laser microdissection and analyzed the samples by a label-free mass spectrometry approach. A total of 390 proteins were identified, and 31 of those showed significantly higher spectral indices in aggregates compared with patient controls with a ratio >1.8. These proteins included filamin C, other known myofibrillar myopathy associated proteins, and a striking number of filamin C binding partners. Across the patients the patterns were extremely homogeneous. Xin actin-binding repeat containing protein 2, heat shock protein 27, nebulin-related-anchoring protein, and Rab35 could be verified as new filaminopathy biomarker candidates. In addition, further experiments identified heat shock protein 27 and Xin actin-binding repeat containing protein 2 as novel filamin C interaction partners and we could show that Xin actin-binding repeat containing protein 2 and the known interaction partner Xin actinbinding repeat containing protein 1 simultaneously associate with filamin C. Ten proteins showed significant lower spectral indices in aggregate samples compared with patient controls (ratio <0.56) including M-band proteins myomesin-1 and myomesin-2. Proteomic findings were consistent with previous and novel immunolocalization data. Our findings suggest that aggregates in filaminopathy have a largely organized structure of proteins also interacting under physiological conditions. Different filamin C mutations seem to lead to almost identical aggregate compositions. The finding that filamin C was detected as highly abundant protein in aggregates in filaminopathy indicates that our proteomic approach may be suitable to identify new candidate genes among the many MFM patients with so far unknown mutation. Molecular & Cellular Proteomics

Dynamic intraligamentary stabilisation presents a promising treatment option for acute ACL ruptures, eliminating the need for ACL reconstruction. Cite this article: Bone Joint J 2016;98-B:793-8.

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