Human lumbar CSF patterns of Ab peptides were analysed by urea-based b-amyloid sodium dodecyl sulphate polyacrylamide gel electrophoresis with western immunoblot (Ab-SDS-PAGE/immunoblot). A highly conserved pattern of carboxyterminally truncated Ab1-37/38/39 was found in addition to Ab1-40 and Ab1-42. Remarkably, Ab1-38 was present at a higher concentration than Ab1-42, being the second prominent Ab peptide species in CSF. Patients with Alzheimer's disease (AD, n ¼ 12) and patients with chronic inflammatory CNS disease (CID, n ¼ 10) were differentiated by unique CSF Ab peptide patterns from patients with other neuropsychiatric diseases (OND, n ¼ 37). This became evident only when we investigated the amount of Ab peptides relative to their total Ab peptide concentration (Ab1-x%, fractional Ab peptide pattern), which may reflect diseasespecific c-secretase activities. Remarkably, patients with AD and CID shared elevated Ab1-38% values, whereas otherwise the patterns were distinct, allowing separation of AD from CID or OND patients without overlap. The presence of one or two ApoE e4 alleles resulted in an overall reduction of CSF Ab peptides, which was pronounced for Ab1-42. The severity of dementia was significantly correlated to the fractional Ab peptide pattern but not to the absolute Ab peptide concentrations. Keywords: Alzheimer's disease (AD), b-amyloid protein precursor/metabolism, biological markers, cerebrospinal fluid, 2D-PAGE, western immunoblot.

The γ-secretase complex plays a role in Alzheimer’s disease (AD) and cancer progression. The development of clinical useful inhibitors, however, is complicated by the role of the γ-secretase complex in regulated intramembrane proteolysis of Notch and other essential proteins. Different γ-secretase complexes containing different Presenilin or Aph1 protein subunits are present in various tissues. Here we show that these complexes have heterogeneous biochemical and physiological properties. Specific inactivation of the Aph1B γ-secretase in a murine Alzheimer’s disease model led to improvements of Alzheimer’s disease-relevant phenotypic features without any Notch-related side effects. The Aph1B complex contributes to total γ-secretase activity in the human brain, thus specific targeting of Aph1B-containing γ-secretase complexes may be helpful in generating less toxic therapies for Alzheimer’s disease.

Mice lacking the receptor tyrosine kinase c-Kit (c-Kit(W/W)) have hematopoietic defects causing perinatal death. We have identified a viable c-Kit(W/W) mouse, termed the "Vickid" mouse. Around birth, c-Kit plays a redundant role in T and no role in B cell development. Here, we show an age-dependent, progressive decline of pro-T and pro-B cells accompanied by loss of common lymphoid progenitors in the bone marrow in adult mice lacking c-Kit. Adult c-Kit(W/W) hematopoietic stem cells can engraft in host bone marrow but fail to radioprotect, form spleen colonies, or establish sustained lymphopoiesis. These defects in adult T and B cell development are also evident in a second viable c-Kit(W/W) strain, rescued by overexpression of erythropoietin.

The thymus is organized into medullary and cortical zones that support distinct stages of T-cell development. The formation of medulla and cortex compartments is thought to occur through invagination of an endodermal epithelial sheet into an ectodermal one at the third pharyngeal pouch and cleft, respectively. Epithelial stem/progenitor cells have been proposed to be involved in thymus development, but evidence for their existence has been elusive. We have constructed chimaeric mice by injecting embryonic stem (ES) cells into blastocysts using ES cells and blastocysts differing in their major histocompatibility complex (MHC) type. Here we show that the MHC class-II-positive medullary epithelium in these chimaeras is composed of cell clusters, most of which derive from either embryonic stem cell or blastocyst, but not mixed, origin. Thus, the medulla comprises individual epithelial 'islets' each arising from a single progenitor. One thymic lobe has about 300 medullary areas that originate from as few as 900 progenitors. Islet formation can be recapitulated after implantation of 'reaggregated fetal thymic organs' into mice, which shows that medullary 'stem' cells retain their potential until at least day 16.5 in fetal development. Thus, medulla-cortex compartmentalization is established by formation of medullary islets from single progenitors.