Genetic suppression of transgenic APP rescues hypersynchronous network activity in a mouse model of alzeimer\u27s 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 β (Aβ) 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 Aβ 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 Aβ overproduction, is responsible for EEG abnormalities in our transgenic mice and can be rescued independently of pathology

Axin determines cell fate by controlling the p53 activation threshold after DNA damage

Cells can undergo either cell-cycle arrest or apoptosis after genotoxic stress, based on p53 activity(1-6). Here we show that cellular fate commitment depends on Axin forming distinct complexes with Pirh2, Tip60, HIPK2 and p53. In cells treated with sublethal doses of ultra-violet (UV) radiation or doxorubicin (Dox), Pirh2 abrogates Axin-induced p53 phosphorylation at Ser 46 catalysed by HIPK2, by competing with HIPK2 for binding to Axin. However, on lethal treatment, Tip60 interacts with Axin and abrogates Pirh2-Axin binding, forming an Axin-Tip60-HIPK2-p53 complex that allows maximal p53 activation to trigger apoptosis. We also provide evidence that the ATM/ATR pathway mediates the Axin-Tip60 complex assembly. An axin mutation promotes carcinogenesis in Axin(Fu)/+ (Axin-Fused) mice, consistent with a dominant-negative role for Axin(Fu) in p53 activation. Thus, Axin is a critical determinant in p53-dependent tumour suppression in which Pirh2 and Tip60 have different roles in triggering cell-cycle arrest or apoptosis depending on the severity of genotoxic stress.973 Program and 863 Program National Natural Science Foundation of China Ministry of Education of China National Basic Research Program of the Ministry of Science and Technology National Science Foundation of Fujian Provinc

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

Modeling Alzheimer’s Disease in Mouse without Mutant Protein Overexpression: Cooperative and Independent Effects of Aβ and Tau

<div><p>Background</p><p>Alzheimer’s disease (AD), the most common cause of dementia in the elderly, has two pathological hallmarks: Aβ plaques and aggregation of hyperphosphorylated tau (p-tau). Aβ 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 Aβ production. Genetic mutations in <i>APP</i>, PSEN1 or <i>PSEN2</i> 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. </p> <p>Results</p><p>To model AD pathophysiology in mice without the gross overexpression of mutant transgenes, we created a humanized AD mouse model by crossing the <i>APP</i> and <i>PSEN1</i> FAD knock-in mice with the htau mice which express wildtype human <i>MAPT</i> genomic DNA on mouse <i>MAPT</i> null background (APP/PS1/htau). The APP/PS1/htau mice displayed mild, age-dependent, Aβ 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 Aβ ELISA, were performed to study the interaction between Aβ 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 Aβ and p-tau, and it can be completely abolished by tau deletion.</p> <p>Conclusion</p><p>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 Aβ and p-tau. </p> </div

Plaque pathology increases with age in APP/PS1 and APP/PS1/htau animals.

<p>A. Immunohistochemical staining of 18-22 month-old WT, APP/PS1, htau, APP/PS1/htau brains. WT and htau brains are free of plaques. Scattered plaque deposition (black arrows) is detected in the outer layer of cortex in APP/PS1 and APP/PS1/htau brains, but not in hippocampus at this point. B. Immunohistochemical staining of 26-29 month-old APP/PS1 and APP/PS1/htau brains. Plaques have progressed into inner layers of cortex and become detectable in hippocampus. C. The brain plaque load in APP/PS1 and APP/PS1/htau samples at 18-22 and at 26-29 months of age. D. Aβ and p-tau double-labeling in APP/PS1/htau sections. Immunofluorescence staining of brain sections from 29 month-old APP/PS1/htau mice. Co-presence of p-tau (green) and Aβ plaque (red) with DAPI (blue) is shown in cortex, and hippocampus.</p

Immunofluorescence staining showing tau phosphorylation in the cortex and hippocampus of knock-in animals at 18 to 22 months of age.

<p>A. Frozen brain sections from WT, APP/PS1, htau, and APP/PS1/htau animals were stained against phosphorylated tau (CP13, green; DAPI, blue). Images were captured using 20X objective lens. Compared to WT, increased tau phosphorylation is present in htau and APP/PS1/htau animals, but not in APP/PS1 animals. Scale bar, 200µm. B. Images captured using 40X objective lens show structural details of phosphorylated tau (CP13, green; DAPI, blue) in htau, and APP/PS1/htau animals. Scale bar, 50µm. C&D. Quantification of fluorescence intensity of cortex and hippocampus from WT, APP/PS1, htau, and APP/PS1/htau brain sections. </p

APP/PS1/htau animals did not show obvious learning and memory deficits in the Morris water maze test at 12 months of age.

<p>A. The learning curve. B-D. Probe test quantified with swimming time, swimming distance, and number of platform crossings. The target quadrant (Quadrant-3) is marked with **. N=12/group.</p

APP/PS1/htau animals showed age-dependent reduced activity and exaggerated fear response that can be ameliorated by tau deletion.

<p>A. The total travel distance (TOTD) was measured from WT, APP, APP/PS1 and APP/PS1/htau males at 4 and 12 months of age. At 4 months of age, there was no difference across different groups; but at 12 months of age, the locomotor activity was greatly reduced in APP/PS1 and APP/PS1/htau animals. # p< 0.06, *p<0.05, student t-test. B. Pre-shock baseline was measured immediately after the animals were put into the test chamber for the first time before any sound or shock stimuli. C. Contextual freezing. There was no difference between the WT and APP group, but the freezing frequency was significantly increased in the APP/PS1 group and further increased in the APP/PS1/htau group at both 4 and 12 months of age. D. Cued freezing frequency was calculated by subtracting the post-shock baseline from the observed freezing to the sound. There was no significant difference across all groups at both ages. *p<0.05, **p<0.01, ***p<0.001, student t-test. N=10-18/group. E. Contextual freezing of an independent cohort of WT, APP/PS1/htau, APP/PS1/tau-/-, htau, and tau-/- animals at a young age was measured. Compared to APP/PS1/htau animals, tau deletion in APP/PS1/tau-/- mice significantly reduced the freezing frequency to the WT level. htau and tau-/- animals show no significant change in freezing frequency. F. Cued freezing frequency remains the same across all the groups tested. *p<0.05, **p<0.01, student t-test. N=9-13/group.</p

γ-secretase activity and Aβ levels are not affected by the presence of htau.

<p>A-C. Brain lysates from WT, APP, PS1, APP/PS1, and APP/PS1/htau animals at 3 to 4 months of age were analyzed using γ-secretase activity assay. PS1 M146V mutation does not alter Aβ40 but significantly increases Aβ42 production, leading to increased Aβ42:Aβ40 ratio in PS1, APP/PS1, and APP/PS1/htau samples. However, no significant difference in γ-secretase activity was found between PS1, APP/PS1, APP/PS1/htau samples. *** p<0.001, one-way ANOVA with Newman-Keuls multiple comparison test. D-F. Aβ ELISA was performed using brain lysates from APP/PS1 and APP/PS1/htau animals. Presence of htau does not change Aβ40 or Aβ42 production. Student t-test, no significant difference.</p