The familial Alzheimer's disease gene product amyloid ␤ precursor protein (APP) is sequentially processed by ␤-and ␥-secretases to generate the A␤ peptide. The biochemical pathway leading to A␤ formation has been extensively studied since extracellular aggregates of A␤ peptides are considered the culprit of Alzheimer's disease. Aside from its pathological relevance, the biological role of APP processing is unknown. Cleavage of APP by ␥-secretase releases, together with A␤, a COOH-terminal APP intracellular domain, termed AID. This peptide has recently been identified in brain tissue of normal control and patients with sporadic Alzheimer's disease. We have previously shown that AID acts as a positive regulator of apoptosis. Nevertheless, the molecular mechanism by which AID regulates this process remains unknown. Hoping to gain clues about the function of APP, we used the yeast two-hybrid system to identify interaction between the AID region of APP and JNK-interacting protein-1 (JIP1). This molecular interaction is confirmed in vitro, in vivo by fluorescence resonance energy transfer (FRET), and in mouse brain lysates. These data provide a link between APP and its processing by ␥-secretase, and stress kinase signaling pathways. These pathways are known regulators of apoptosis and may be involved in the pathogenesis of Alzheimer's disease. The amyloid ␤ (A␤)1 peptide is the principal component of amyloid plaques in the brain of Alzheimer's disease (AD) patients (1-3). A␤ is derived from APP by two sequential proteolytic events, one in the extracellular domain (␤-secretase cleavage) (4) and one in the transmembrane domain (␥-secretase cleavage) (5). APP processing has become firmly associated with the pathogenesis of AD with the identification of missense mutations in three genes associated with familial forms of AD (FAD). The FAD mutations identified to date are found in APP itself, and in two highly homologous genes now known as presenilin 1 and presenilin 2 (PS1, PS2) (6 -9). Presenilins are a key component of a multimolecular complex with ␥-secretase activity that contains at least one other recently identified protein named nicastrin (10 -16). A common feature of all FAD mutations is that they increase the generation of A␤ peptides (especially the A␤42 form, considered to be more pathogenic than the A␤40 peptide) by accelerating the rate of APP processing by either ␤-or ␥-secretase (5, 18 -20). In addition to the A␤ peptide which is mostly released from the cell, another peptide, AID, is released into the cytoplasm as a result of the ␥-secretase cleavage. Although the role of the A␤ peptide in the pathogenesis of AD has been extensively studied, only recently have there been reports as to the role of AID. AID-like peptides have recently been identified in human brains from normal controls and cases of sporadic AD (21). AID has also been implicated in the pathology of AD by data indicating that it can independently trigger apoptosis or enhance other apoptotic stimuli (21). This may represent the mechanism by wh...

Duplex Doppler sonography is a fundamental component of the complete ultrasonographic examination of the liver. Accurate interpretation of the spectral Doppler tracing from the hepatic veins is valuable, as it reflects important cardiac and hepatic physiology. Normally, there are four phases: A, S, V, and D; the S and D waves indicate flow in the antegrade direction toward the heart. In hepatic and cardiac disease, these normal waves may be absent, a finding indicative of flow in a nonphysiologic manner. In addition, transient patient factors such as phase of the respiratory cycle may influence the appearance of the spectral tracing. Familiarity with the normal and abnormal spectral Doppler waveforms from the hepatic veins and knowledge of their respective physiology and pathophysiology provide valuable insights. Systematic analysis of the direction, regularity, and phasicity of the spectral tracing and the ratio of the amplitudes of the S and D waves allows one to arrive at the correct differential diagnosis in most situations.

The ␤-amyloid precursor protein (APP) and the Notch receptor undergo intramembranous proteolysis by the Presenilin-dependent ␥-secretase.