Background: Beta amyloid (Aβ) peptides are the major constituents of the senile plaques present in Alzheimer's diseased brain. Pathogenesis has been associated with the aggregated form of the peptide as these fibrils are the conformation readily found in the plaques. However, recent studies have shown that the nonaggregated, soluble assemblies of Aβ have the potential to stimulate neuronal dysfunction and may play a prominent role in the pathogenesis of Alzheimer's disease.

Alzheimer's disease is a progressive neurodegenerative disorder characterized by extracellular deposition of ␤-amyloid (A␤) peptide containing neuritic plaques. A␤ peptides are proteolytically derived from the membrane-bound amyloid precursor protein (APP). Although the function of APP is not entirely clear, previous studies demonstrate that neuronal APP colocalizes with ␤ 1 integrin receptors at sites of focal adhesion, suggesting that APP is involved in mediating neuronal process adhesion. Integrin-dependent adhesion is also a well-characterized component of immune cell proinflammatory activation. Using primary mouse microglia and the human monocytic cell line, THP-1, we have begun investigating the role of APP in integrin-dependent activation. Co-immunoprecipitation studies demonstrate that APP is recruited into a multi-receptor signaling complex during ␤ 1 integrin-mediated adhesion of monocytes. Stimulation induces a subsequent, specific recruitment of tyrosine phosphorylated proteins to APP, including Lyn and Syk. Antibody cross-linking of cell surface APP leads to a similar response characterized by activation and recruitment of tyrosine kinases to APP as well as subsequent activation of mitogen-activated protein kinases and increased proinflammatory protein levels. These data demonstrate that APP can act as a proinflammatory receptor in monocytic lineage cells and provide insight into the contribution of this protein to the inflammatory conditions described in Alzheimer's disease.Amyloid precursor protein (APP) 1 is a ubiquitously expressed integral membrane protein from which the 1-40 and 1-42 residue ␤-amyloid (A␤) peptides are proteolytically cleaved (1). The longer, more insoluble peptide, A␤1-42, is a marked component of the extracellular neuritic plaques characteristic of Alzheimer's disease (2). The physiologic role for APP independent of the production of the A␤ peptides remains to be elucidated.Although only a fraction of the pool of cellular APP localizes to the plasma membrane, the overall structure of the protein suggests that APP may function as a receptor or growth factor (3). APP is an integral transmembrane glycoprotein that exists as one of three major splice variants consisting of either 695, 751, or 770 amino acid residues (4). These isoforms are composed of a large glycosylated extracellular region, a single membrane-spanning domain, and a short, highly conserved cytoplasmic tail (1). Interestingly, the cytoplasmic domain of APP contains a well-defined consensus motif found in tyrosine kinase receptors, NPXY, implicating a role in signal transduction that is reinforced by the ability of multiple adaptor proteins including Fe65 and X11 to interact with this specific motif on neuronal APP (5-7). The phosphotyrosine-binding domains of Fe65 and X11 bind the phosphotyrosine binding motif (Y 682 ENPTY 687 ) on the intracellular domain of APP. However, there is no evidence that phosphorylation of this domain is required for the interaction to occur (8, 9). The adaptor protein Shc has also be...

Bariatric surgery is currently the most effective intervention for significant and sustained weight loss in obese individuals. While patients often realize numerous improvements in obesity-related comorbidities and health-related quality of life, a small minority of patients have less optimal outcomes following bariatric surgery. The literature on the emergence of alcohol use disorders (AUDs) following bariatric surgery has grown in the past several years and collectively provides convincing evidence that a significant minority of patients develop new-onset AUDs following bariatric surgery. Rouxen-Y gastric bypass (RYGB) has generally been associated with the risk of developing an AUD, while laparoscopic adjustable gastric banding generally has not, in several large studies. One theory that has been discussed at some length is the idea of 'addiction transfer' wherein patients substitute one 'addiction' (food) for a new 'addiction' (alcohol) following surgery. Animal work suggests a neurobiological basis for increased alcohol reward following RYGB. In addition, several pharmacokinetic studies have shown rapid and dramatically increased peak alcohol concentrations following RYGB. The prevalence of alcohol and other addictive disorders and potential etiological contributors to post-operative AUDs will be explored.

Background Recent literature suggests that some patients may develop addictive disorders after bariatric surgery, in particular following Roux-en-Y gastric bypass (RYGB). These may include traditional addictions and so called “behavioral addictions”, although prevalence data on the latter have not been published. Objectives To establish prevalence of addictive behaviors in adults following RYGB. Setting 2 university hospitals and 1 not-for-profit research institute in the U.S. Methods Participants from a large observational study of bariatric surgery who had undergone RYGB were recruited to complete additional measures. Of 241 consented participants, 201 provided data (i.e., Structured Clinical Interview for DSM-IV Axis I [SCID], additional Impulsive Control Disorder Modules, and various self-report measures, including the Alcohol Use Disorder Identification Test [AUDIT]) to assess status prior to surgery and in the first three post-operative years.). Results Based on the SCID, 16 (8.0%) developed alcohol use disorder [AUD] within three years post-RYGB, 7 (43.8%) of whom had no history of AUD. When both the SCID and AUDIT were used to identify AUD, the corresponding numbers/percentages were 32 (18.4%) and 13 (40.6%). Data on other behavioral addictive disorders indicated 19 (9.5%) had a post-surgery disorder, 6 (31.6%) of whom had no history. Conclusions These data add to a growing literature suggesting there is a substantial risk for the development of AUD after bariatric surgery. Understanding the risk for non-drug related addictive disorders requires more data from larger studies before clear conclusions can be drawn.