The familial Alzheimer's disease gene product ␤-amyloid (A␤) precursor protein (APP) is processed by the ␤-and ␥-secretases to produce A␤ as well as AID (APP Intracellular Domain) which is derived from the extreme carboxyl terminus of APP. AID was originally shown to lower the cellular threshold to apoptosis and more recently has been shown to modulate gene expression such that it represses Notch-dependent gene expression while in combination with Fe65 it enhances gene activation. Here we report that the two other members of the APP family, ␤-amyloid precursor-like protein-1 and -2 (APLP1 and APLP2), are also processed by the ␥-secretase in a Presenilin 1-dependent manner. Furthermore, the extreme carboxyl-terminal fragments produced by this processing (here termed APP-like Intracellular Domain or ALID1 and ALID2) are able to enhance Fe65-dependent gene activation, similar to what has been reported for AID. Considering that only APP and not the APLPs have been linked to familial Alzheimer's disease (AD), this data should help in understanding the physiologic roles of the APP family members and in differentiating these functions from the pathologic role of APP in Alzheimer's disease.The APP 1 family consists of three family members, APP, APLP1, and APLP2 (1-4). Most research on the family has been focused on APP because it has been directly implicated in Alzheimer's disease (5, 6). APP undergoes extensive proteolytic processing along two major pathways. APP can be cleaved extracellularly by the ␣-secretase creating a C83 membranebound intermediate, which is subsequently cleaved by the ␥-secretase releasing a non-amyloidogenic fragment termed p3. Alternatively, APP can be cleaved extracellularly by the ␤-secretase forming a C99 membrane-bound intermediate, which is subsequently cleaved by the ␥-secretase releasing the amyloidogenic A␤ fragment. A␤ is the major component of the amyloid plaques found in the brains of patients with AD and is considered to be the major underlying cause of the disease. An additional peptide termed AID, extending from the ␥-secretase cleavage site to the carboxyl terminus of APP, is also produced following ␥-secretase cleavage regardless of whether it was preceded by ␣ or ␤ cleavage. This AID peptide was first identified in the brains of patients with AD and normal controls, and was shown to either induce or sensitize cells to apoptosis (7,8). More recently AID has been found to participate in transcription (9 -12) by activating gene expression in combination with Fe65 and repressing activation of genes induced by Notch. These data have opened the important possibility that just as Notch undergoes regulated intramembranous proteolysis (13) by the ␥-secretase, so does APP.Much less is known about APLP1 and APLP2, the two other APP family members. The human APLP1 gene is located on chromosome 19q13.1 (14), and APLP2 is located on chromosome 11q23-q25 (15). Although no clear neuronal functions have been found for these molecules, APLP1 has been implicated in synaptogenesis (16), and recomb...

The intestinal mucosa is suggested to support extrathymic T cell development, particularly for T cell receptor (TCR)-γδ intraepithelial lymphocytes (IELs). TCR-γδ cell development requires interleukin (IL)-7; IL-7−/− or IL-7 receptor−/− mice lack TCR-γδ cells. Using the intestinal fatty acid binding protein (iFABP) promoter, we reinstated expression of IL-7 to mature enterocytes of IL-7−/− mice (iFABP-IL7). In iFABP-IL7 mice, TCR-γδ IELs were restored, as were cryptopatches and Peyer's patches. TCR-γδ cells remained absent from all other tissues. Likewise, T cell development in thymus and B cell maturation in the bone marrow and spleen retained the IL-7−/− phenotype. Thus, IL-7 expression by enterocytes was sufficient for extrathymic development of TCR-γδ cells in situ within the intestinal epithelium and was crucial for organization of mucosal lymphoid tissue.

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