Xanthogranulomatous inflammation involving the gallbladder, bile duct, and pancreas: a case report.

Xanthogranulomatous inflammation (XGI) is a rare, benign condition that can affect several organs, including the gallbladder, kidney, skin, gastrointestinal tract, lymph nodes, and soft tissues. It is often misdiagnosed as a malignancy. In this report, we present the case of a 79-year-old male who presented with persistent jaundice for 11 months. Computed tomography and magnetic resonance imaging revealed pancreatic head enlargement, gallbladder thickening, and common bile duct thickening, leading to a preoperative diagnosis of malignant neoplasm of the pancreatic head. During surgery, dense adhesions were found around the portal vein, suggestive of mass invasion. To relieve obstruction, choledochojejunostomy was performed. Postoperative pathological examination revealed xanthogranulomatous cholecystitis (XGCc), xanthogranulomatous cholangitis (XGCg), and xanthogranulomatous pancreatitis (XGP). XGI affecting the bile ducts and pancreas is extremely rare, and there are no reported cases of simultaneous involvement of the gallbladder, bile duct, and pancreas by XGI. This study provides valuable insight into the differential diagnosis of XGI by presenting the imaging features of XGI patients.

Arginine ADP-ribosyltransferase 1 Regulates Glycolysis in Colorectal Cancer via the PI3K/AKT/HIF1α Pathway.

OBJECTIVE: Arginine ADP-ribosyltransferase 1 (ART1) is involved in the regulation of a diverse array of pathophysiological processes, including proliferation, invasion, apoptosis, autophagy and angiogenesis of colorectal cancer (CRC) cells. However, how ART1 regulates glycolysis in CRC remains elusive. METHODS: To elucidate the role of ART1 in glycolysis in CRC, we assessed the protein level of ART1, hypoxia-inducible factor 1α (HIF1α), and glucose transporter type 1 (GLUT1) in 61 CRC tumor tissue specimens obtained from patients with different 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) uptake as analyzed by PET/CT before surgery. Colon adenocarcinoma CT26 cells with ART1 knockdown and overexpression were established, respectively, and the molecular mechanism underlying the effect of ART1 on glycolysis in CRC was determined both in vivo and in vitro. RESULTS: The expression of ART1 and GLUT1 was significantly associated with FDG uptake (P=0.037 and P=0.022, respectively) in CRC tissues. Furthermore, the expression of hexokinase 2 (HK2) and lactate dehydrogenase (LDH) was upregulated in ART1-overexpressed CT26 cells, but was downregulated in ART1-knockdown CT26 cells. The volume and weight of subcutaneously transplanted tumors were markedly increased in the ART1-overexpressed BALB/c mice group and decreased in the ART1-knockdown group. In CT26 cells, the overexpression of ART1 promoted the expression levels of HK2 and LDH, and knockdown of ART1 suppressed them in the CT26 tumors. In both normal and hypoxic conditions, ART1 expression was associated with the protein level of phospho-serine/threonine kinase (p-AKT), HIF1α, and GLUT1 but not with that of AKT in CT26 cells and subcutaneous transplanted tumors. CONCLUSION: ART1 plays a crucial role in the elevation of glucose consumption in CT26 cells and may regulate GLUT1-dependent glycolysis in CRC via the PI3K/AKT/HIF1α pathway.

Vascular and parenchymal amyloid pathology in an Alzheimer disease knock-in mouse model: interplay with cerebral blood flow.

BACKGROUND: Accumulation and deposition of ß-amyloid peptides (Aß) in the brain is a central event in the pathogenesis of Alzheimer's disease (AD). Besides the parenchymal pathology, Aß is known to undergo active transport across the blood-brain barrier and cerebral amyloid angiopathy (CAA) is a prominent feature in the majority of AD. Although impaired cerebral blood flow (CBF) has been implicated in faulty Aß transport and clearance, and cerebral hypoperfusion can exist in the pre-clinical phase of Alzheimer's disease (AD), it is still unclear whether it is one of the causal factors for AD pathogenesis, or an early consequence of a multi-factor condition that would lead to AD at late stage. To study the potential interaction between faulty CBF and amyloid accumulation in clinical-relevant situation, we generated a new amyloid precursor protein (APP) knock-in allele that expresses humanized Aß and a Dutch mutation in addition to Swedish/London mutations and compared this line with an equivalent knock-in line but in the absence of the Dutch mutation, both crossed onto the PS1M146V knock-in background. RESULTS: Introduction of the Dutch mutation results in robust CAA and parenchymal Aß pathology, age-dependent reduction of spatial learning and memory deficits, and CBF reduction as detected by fMRI. Direct manipulation of CBF by transverse aortic constriction surgery on the left common carotid artery caused differential changes in CBF in the anterior and middle region of the cortex, where it is reduced on the left side and increased on the right side. However these perturbations in CBF resulted in the same effect: both significantly exacerbate CAA and amyloid pathology. CONCLUSIONS: Our study reveals a direct and positive link between vascular and parenchymal Aß; both can be modulated by CBF. The new APP knock-in mouse model recapitulates many symptoms of AD including progressive vascular and parenchymal Aß pathology and behavioral deficits in the absence of APP overexpression.

Genetic suppression of transgenic APP rescues Hypersynchronous network activity in a mouse model of Alzeimer's disease.

Alzheimer's disease (AD) is associated with an elevated risk for seizures that may be fundamentally connected to cognitive dysfunction. Supporting this link, many mouse models for AD exhibit abnormal electroencephalogram (EEG) activity in addition to the expected neuropathology and cognitive deficits. Here, we used a controllable transgenic system to investigate how network changes develop and are maintained in a model characterized by amyloid ß (Aß) overproduction and progressive amyloid pathology. EEG recordings in tet-off mice overexpressing amyloid precursor protein (APP) from birth display frequent sharp wave discharges (SWDs). Unexpectedly, we found that withholding APP overexpression until adulthood substantially delayed the appearance of epileptiform activity. Together, these findings suggest that juvenile APP overexpression altered cortical development to favor synchronized firing. Regardless of the age at which EEG abnormalities appeared, the phenotype was dependent on continued APP overexpression and abated over several weeks once transgene expression was suppressed. Abnormal EEG discharges were independent of plaque load and could be extinguished without altering deposited amyloid. Selective reduction of Aß with a γ-secretase inhibitor has no effect on the frequency of SWDs, indicating that another APP fragment or the full-length protein was likely responsible for maintaining EEG abnormalities. Moreover, transgene suppression normalized the ratio of excitatory to inhibitory innervation in the cortex, whereas secretase inhibition did not. Our results suggest that APP overexpression, and not Aß overproduction, is responsible for EEG abnormalities in our transgenic mice and can be rescued independently of pathology.

Modeling Alzheimer's disease in mouse without mutant protein overexpression: cooperative and independent effects of Aß and tau.

BACKGROUND: Alzheimer's disease (AD), the most common cause of dementia in the elderly, has two pathological hallmarks: Aß plaques and aggregation of hyperphosphorylated tau (p-tau). Aß is a cleavage product of Amyloid Precursor Protein (APP). Presenilin 1 (PS1) and presenilin 2 (PS2) are the catalytic subunit of γ-secretase, which cleaves APP and mediates Aß production. Genetic mutations in APP, PSEN1 or PSEN2 can lead to early onset of familial AD (FAD). Although mutations in the tau encoding gene MAPT leads to a subtype of frontotemporal dementia and these mutations have been used to model AD tauopathy, no MAPT mutations have been found to be associated with AD. RESULTS: To model AD pathophysiology in mice without the gross overexpression of mutant transgenes, we created a humanized AD mouse model by crossing the APP and PSEN1 FAD knock-in mice with the htau mice which express wildtype human MAPT genomic DNA on mouse MAPT null background (APP/PS1/htau). The APP/PS1/htau mice displayed mild, age-dependent, Aß plaques and tau hyperphosphorylation, thus successfully recapitulating the late-onset AD pathological hallmarks. Selected biochemical analyses, including p-tau western blot, γ-secretase activity assay, and Aß ELISA, were performed to study the interaction between Aß and p-tau. Subsequent behavioral studies revealed that the APP/PS1/htau mice showed reduced mobility in old ages and exaggerated fear response. Genetic analysis suggested that the fear phenotype is due to a synergic interaction between Aß and p-tau, and it can be completely abolished by tau deletion. CONCLUSION: The APP/PS1/htau model represents a valuable and disease-relevant late-onset pre-clinical AD animal model because it incorporates human AD genetics without mutant protein overexpression. Analysis of the mice revealed both cooperative and independent effects of Aß and p-tau.

Central CRF system perturbation in an Alzheimer's disease knockin mouse model.

Alzheimer's disease (AD) is often accompanied by changes in mood as well as increases in circulating cortisol levels, suggesting that regulation of the stress responsive hypothalamic-pituitary-adrenal (HPA) axis is disturbed. Here, we show that amyloid precursor protein (APP) is endogenously expressed in important limbic, hypothalamic, and midbrain nuclei that regulate hypothalamic-pituitary-adrenal axis activity. Furthermore, in a knockin mouse model of AD that expresses familial AD (FAD) mutations of both APP with humanized amyloid beta (hAß), and presenilin 1 (PS1), in their endogenous patterns (APP/hAß/PS1 animals), corticotropin releasing factor (CRF) levels are increased in key stress-related nuclei, resting corticosteroid levels are elevated, and animals display increased anxiety-related behavior. Endocrine and behavioral phenotypes can be normalized by loss of 1 copy of CRF receptor type-1 (Crfr1), consistent with a perturbation of central CRF signaling in APP/hAß/PS1 animals. However, reductions in anxiety and corticosteroid levels conferred by heterozygosity of CRF receptor type-1 do not improve a deficit in working memory observed in APP/hAß/PS1 mice, suggesting that perturbations of the CRF system are not the primary cause of decreased cognitive performance.

APP physiological and pathophysiological functions: insights from animal models.

The amyloid precursor protein (APP) has been under intensive study in recent years, mainly due to its critical role in the pathogenesis of Alzheimer's disease (AD). ß-Amyloid (Aß) peptides generated from APP proteolytic cleavage can aggregate, leading to plaque formation in human AD brains. Point mutations of APP affecting Aß production are found to be causal for hereditary early onset familial AD. It is very likely that elucidating the physiological properties of APP will greatly facilitate the understanding of its role in AD pathogenesis. A number of APP loss- and gain-of-function models have been established in model organisms including Caenorhabditis elegans, Drosophila, zebrafish and mouse. These in vivo models provide us valuable insights into APP physiological functions. In addition, several knock-in mouse models expressing mutant APP at a physiological level are available to allow us to study AD pathogenesis without APP overexpression. This article will review the current physiological and pathophysiological animal models of APP.

Amyloid precursor protein revisited: neuron-specific expression and highly stable nature of soluble derivatives.

APP processing and amyloid-ß production play a central role in Alzheimer disease pathogenesis. APP has been considered a ubiquitously expressed protein. In addition to amyloid-ß, α- or ß-secretase-dependent cleavage of APP also generates soluble secreted APP (APPsα or APPsß, respectively). Interestingly, APPsß has been shown to be subject to further cleavage to create an N-APP fragment that binds to the DR6 death receptor and mediates axon pruning and degeneration under trophic factor withdrawal conditions. By performing APP immunocytochemical staining, we found that, unexpectedly, many antibodies yielded nonspecific staining in APP-null samples. Screening of a series of antibodies allowed us to identify a rabbit monoclonal antibody Y188 that is highly specific for APP and prompted us to re-examine the expression, localization, and stability of endogenous APP and APPsß in wild-type and in APPsß knock-in mice, respectively. In contrast to earlier studies, we found that APP is specifically expressed in neurons and that its expression cannot be detected in major types of glial cells under basal or neuroinflammatory conditions. Both APPsα and APPsß are highly stable in the central nervous system (CNS) and do not undergo further cleavage with or without trophic factor support. Our results clarify several key questions with regard to the fundamental properties of APP and offer critical cellular insights into the pathophysiology of APP.

Soluble amyloid precursor protein (APP) regulates transthyretin and Klotho gene expression without rescuing the essential function of APP.

Amyloidogenic processing of the amyloid precursor protein (APP) generates a large secreted ectodomain fragment (APPsß), ß-amyloid (Aß) peptides, and an APP intracellular domain (AICD). Whereas Aß is viewed as critical for Alzheimer's disease pathogenesis, the role of other APP processing products remains enigmatic. Of interest, the AICD has been implicated in transcriptional regulation, and N-terminal cleavage of APPsß has been suggested to produce an active fragment that may mediate axonal pruning and neuronal cell death. We previously reported that mice deficient in APP and APP-like protein 2 (APLP2) exhibit early postnatal lethality and neuromuscular synapse defects, whereas mice with neuronal conditional deletion of APP and APLP2 are viable. Using transcriptional profiling, we now identify transthyretin (TTR) and Klotho as APP/APLP2-dependent genes whose expression is decreased in loss-of-function states but increased in gain-of-function states. Significantly, by creating an APP knockin allele that expresses only APPsß protein, we demonstrate that APPsß is not normally cleaved in vivo and is fully capable of mediating the APP-dependent regulation of TTR and Klotho gene expression. Despite being an active regulator of gene expression, APPsß did not rescue the lethality and neuromuscular synapse defects of APP and APLP2 double-KO animals. Our studies identify TTR and Klotho as physiological targets of APP that are regulated by soluble APPsß independent of developmental APP functions. This unexpected APP-mediated signaling pathway may play an important role in maintaining TTR and Klotho levels and their respective functions in Aß sequestration and aging.

Genetic dissection of the amyloid precursor protein in developmental function and amyloid pathogenesis.

Proteolytic processing of the amyloid precursor protein (APP) generates large soluble APP derivatives, ß-amyloid (Aß) peptides, and APP intracellular domain. Expression of the extracellular sequences of APP or its Caenorhabditis elegans counterpart has been shown to be sufficient in partially rescuing the CNS phenotypes of the APP-deficient mice and the lethality of the apl-1 null C. elegans, respectively, leaving open the question as what is the role of the highly conserved APP intracellular domain? To address this question, we created an APP knock-in allele in which the mouse Aß sequence was replaced by the human Aß. A frameshift mutation was introduced that replaced the last 39 residues of the APP sequence. We demonstrate that the C-terminal mutation does not overtly affect APP processing and amyloid pathology. In contrast, crossing the mutant allele with APP-like protein 2 (APLP2)-null mice results in similar neuromuscular synapse defects and early postnatal lethality as compared with mice doubly deficient in APP and APLP2, demonstrating an indispensable role of the APP C-terminal domain in these development activities. Our results establish an essential function of the conserved APP intracellular domain in developmental regulation, and this activity can be genetically uncoupled from APP processing and Aß pathogenesis.

Presynaptic and postsynaptic interaction of the amyloid precursor protein promotes peripheral and central synaptogenesis.

A critical role of the amyloid precursor protein (APP) in Alzheimer's disease (AD) pathogenesis has been well established. However, the physiological function of APP remains elusive and much debated. We reported previously that the APP family of proteins is essential in mediating the developing neuromuscular synapse. In the current study, we created a conditional allele of APP and deleted APP in presynaptic motor neuron or postsynaptic muscle. Crossing these alleles onto the APP-like protein 2-null background reveals that, unexpectedly, inactivating APP in either compartment results in neuromuscular synapse defects similar to the germline deletion and that postsynaptic APP is obligatory for presynaptic targeting of the high-affinity choline transporter and synaptic transmission. Using a HEK293 and primary hippocampus mixed-culture assay, we report that expression of APP in HEK293 cells potently promotes synaptogenesis in contacting axons. This activity is dependent on neuronal APP and requires both the extracellular and intracellular domains; the latter forms a complex with Mint1 and Cask and is replaceable by the corresponding SynCAM (synaptic cell adhesion molecule) sequences. These in vitro and in vivo studies identify APP as a novel synaptic adhesion molecule. We postulate that transsynaptic APP interaction modulates its synaptic function and that perturbed APP synaptic adhesion activity may contribute to synaptic dysfunction and AD pathogenesis.

A membrane-associated Mn-superoxide dismutase protects the photosynthetic apparatus and nitrogenase from oxidative damage in the Cyanobacterium Anabaena sp. PCC 7120.

We investigated the functions of a membrane-associated manganese superoxide dismutase (MnSOD) of the heterocystous cyanobacterium Anabaena sp. PCC 7120. The gene sodA encoding MnSOD was inactivated by interposon mutagenesis and it was confirmed by Southern hybridization and immunoblotting. The strain A17, lacking sodA, grew more slowly than the wild type, and the difference in growth rates between the two strains became larger with an increase in growth light intensity. More severe inhibition of growth of A17 was observed when the cells were grown in the absence of combined nitrogen. Complementation of A17 with a full copy of the sodA gene restored the wild-type phenotypes. Strain A17 produced more malondialdehyde than did the wild type, especially under high light intensity, indicating more lipid peroxidation in the absence of MnSOD. A17 was also more susceptible to photoinhibition by a high light, and it was shown that both PSII and PSI were more severely damaged by the photoinhibitory light in A17, suggesting that the MnSOD plays important roles in protection of both photosystems. Immunoblotting revealed that the MnSOD was present in vegetative cells and heterocysts. Light greatly stimulated nitrogenase activity in the wild type under both aerobic and anaerobic conditions, but stimulated nitrogenase activity in A17 only slightly in air. The results suggest that reactive oxygen species produced in heterocysts under aerobic conditions cause the inactivation of nitrogenase in the absence of MnSOD.