CD45 deficiency drives amyloid-ß peptide oligomers and neuronal loss in Alzheimer's disease mice.

Converging lines of evidence indicate dysregulation of the key immunoregulatory molecule CD45 (also known as leukocyte common antigen) in Alzheimer's disease (AD). We report that transgenic mice overproducing amyloid-ß peptide (Aß) but deficient in CD45 (PSAPP/CD45(-/-) mice) faithfully recapitulate AD neuropathology. Specifically, we find increased abundance of cerebral intracellular and extracellular soluble oligomeric and insoluble Aß, decreased plasma soluble Aß, increased abundance of microglial neurotoxic cytokines tumor necrosis factor-α and interleukin-1ß, and neuronal loss in PSAPP/CD45(-/-) mice compared with CD45-sufficient PSAPP littermates (bearing mutant human amyloid precursor protein and mutant human presenilin-1 transgenes). After CD45 ablation, in vitro and in vivo studies demonstrate an anti-Aß phagocytic but proinflammatory microglial phenotype. This form of microglial activation occurs with elevated Aß oligomers and neural injury and loss as determined by decreased ratio of anti-apoptotic Bcl-xL to proapoptotic Bax, increased activated caspase-3, mitochondrial dysfunction, and loss of cortical neurons in PSAPP/CD45(-/-) mice. These data show that deficiency in CD45 activity leads to brain accumulation of neurotoxic Aß oligomers and validate CD45-mediated microglial clearance of oligomeric Aß as a novel AD therapeutic target.

Melatonin treatment restores mitochondrial function in Alzheimer's mice: a mitochondrial protective role of melatonin membrane receptor signaling.

Mitochondrial dysfunction is a hallmark of Alzheimer's disease (AD) and is observed in mutant amyloid precursor protein (APP) transgenic mouse models of familial AD. Melatonin is a potent antioxidant, can prevent toxic aggregation of Alzheimer's beta-amyloid (Aß) peptide and, when taken long term, can protect against cognitive deficits in APP transgenic mice. To study the effects of melatonin on brain mitochondrial function in an AD model, APP/PS1 transgenic mice were treated for 1 month with melatonin. Analysis of isolated brain mitochondria from mice indicated that melatonin treatment decreased mitochondrial Aß levels by two- to fourfold in different brain regions. This was accompanied by a near complete restoration of mitochondrial respiratory rates, membrane potential, and ATP levels in isolated mitochondria from the hippocampus, cortex, or striatum. When isolated mitochondria from untreated young mice were given melatonin, a slight increase in respiratory rate was observed. No such effect was observed in mitochondria from aged mice. In APP-expressing neuroblastoma cells in culture, mitochondrial function was restored by melatonin or by the structurally related compounds indole-3-propionic acid or N(1)-acetyl-N(2)-formyl-5-methoxykynuramine. This restoration was partially blocked by melatonin receptor antagonists indicating melatonin receptor signaling is required for the full effect. Therefore, treatments that stimulate melatonin receptor signaling may be beneficial for restoring mitochondrial function in AD, and preservation of mitochondrial function may an important mechanism by which long term melatonin treatment delays cognitive dysfunction in AD mice.

Delayed levorotation of the heart in traumatic pericardial rupture.

Traumatic pericardial rupture, with complicating cardiac herniation, is an extremely uncommon condition with a high mortality rate. We are reporting our experience with a case of blunt trauma to the chest, secondary to high-impact motor vehicle collision. The preoperative diagnosis of ascending aortic transection was made on subsequent imaging studies for which surgical repair was elected. Upon thoracotomy, a posterior pericardial tear was found to be associated with laterally displaced cardiac axis. Delayed levorotation of the cardiac axis in traumatic pericardial rupture is an uncommon finding and needs to be recognized in a timely manner.

Paraneoplastic encephalitis with leukoencephalopathy in primary fallopian tube carcinoma.

Previous reports of paraneoplastic encephalitis occurring in primary fallopian tube carcinoma have been exclusively classified as paraneoplastic cerebellar degeneration, with MR imaging either unremarkable or demonstrating cerebellar atrophy. We report a case of paraneoplastic encephalitis in a 64-year-old female with primary fallopian tube carcinoma, reminiscent of N-methyl d-aspartate receptor encephalitis, with MR imaging demonstrating bilateral subcortical and deep white matter T2-FLAIR hyperintensities sparing cerebellar and brainstem structures. To our knowledge, this represents the first reported case of noncerebellar paraneoplastic encephalitis related to primary fallopian tube carcinoma.

Presentation of ileal Burkitt lymphoma in children.

Burkitt lymphoma is a highly aggressive form of Non-Hodgkin lymphoma that responds favorably if diagnosed accurately and treated early. Recognition of the various radiologic manifestations of Burkitt lymphoma can help guide the clinician to expedite appropriate chemotherapy. We present two cases that illustrate different radiologic presentations of this aggressive gastrointestinal malignancy in children. Case 1 features a 7-year-old boy who presented to our hospital with recurrent ileocecal intussusception. Case 2 describes a 16-year-old male with history of blood-streaked stools. Ileocectomy was performed in both cases and histologic analysis showed the "starry sky pattern" and t(8;14) translocation, classic for Burkitt lymphoma. Both patients remain disease-free following surgical excision and chemotherapy.

Caffeine increases mitochondrial function and blocks melatonin signaling to mitochondria in Alzheimer's mice and cells.

Caffeine and melatonin have been shown to protect the Swedish mutant amyloid precursor protein (APP(sw)) transgenic mouse model of Alzheimer's disease from cognitive dysfunction. But their mechanisms of action remain incompletely understood. These Alzheimer's mice have extensive mitochondrial dysfunction, which likely contributes to their cognitive decline. To further explore the mechanism through which caffeine and melatonin protect cognitive function in these mice, we monitored the function of isolated mitochondria from APP(sw) mice treated with caffeine, melatonin, or both in their drinking water for one month. Melatonin treatment yielded a near complete restoration of mitochondrial function in assays of respiratory rate, membrane potential, reactive oxygen species production, and ATP levels. Caffeine treatment by itself yielded a small increase in mitochondrial function. However, caffeine largely blocked the large enhancement of mitochondrial function provided by melatonin. Studies with N2a neuroblastoma cells stably expressing APP(sw) showed that specific inhibition of cAMP-dependent phosphodiesterase (PDE) 4 or cGMP-dependent PDE5 also blocked melatonin protection of mitochondrial function, but A(2a) and A1 adenosine receptor antagonists were without effect. Melatonin or caffeine at the concentrations used to modulate mitochondrial function in the cells had no effect on cAMP-dependent PDE activity or cellular cAMP or cGMP levels. Therefore, caffeine and increased cyclic nucleotide levels likely block melatonin signaling to mitochondria by independent mechanisms that do not involve adenosine receptor antagonism. The results of this study indicate that melatonin restores mitochondrial function much more potently than caffeine in APP(sw) transgenic mouse and cell models of Alzheimer's disease.

Gerbode ventricular septal defect diagnosed using cardiac CTA imaging.

This report describes the ability of computed tomography angiography (CTA) imaging of the heart to visualize an acquired shunt between the left ventricular outflow tract (LVOT) and the right atrium (RA) (Gerbode defect). Previously, transesophageal echocardiography (TEE) has been the mainstay of diagnosis. To the best of our knowledge, the use of cardiac CTA imaging to visualize and diagnose this disorder has not been previously reported. Cardiac CTA allows for more detailed visualization of cardiac anatomy and can supplement or supplant TEE as the diagnostic test of choice for evaluation of patients with this rare defect.

Green tea epigallocatechin-3-gallate (EGCG) and other flavonoids reduce Alzheimer's amyloid-induced mitochondrial dysfunction.

Amyloid-ß (Aß)-induced mitochondrial dysfunction may play a role in the onset and progression of Alzheimer's disease (AD). Therefore, therapeutics targeted to improve mitochondrial function could be beneficial. Plant-derived flavonoids have shown promise in improving certain AD phenotypes, but the overall mechanism of action(s) through which flavonoids protect from AD is still unknown. To identify flavonoids and other natural products that may correct amyloid-induced mitochondrial dysfunction, 25 natural products were screened for their ability to restore altered mitochondrial membrane potential (MMP), reactive oxygen species (ROS) production, or ATP levels in neuroblastoma cells expressing mutant amyloid-ß protein precursor (AßPP). Epigallocatechin-3-gallate (EGCG) and luteolin were identified as the top two mitochondrial restorative compounds from the in vitro screen. EGCG was further tested in vivo to determine its effects on brain mitochondrial function in an AßPP/PS-1 (presenilin 1) double mutant transgenic mouse model of AD. EGCG treatment restored mitochondrial respiratory rates, MMP, ROS production, and ATP levels by 50 to 85% in mitochondria isolated from the hippocampus, cortex, and striatum. The results of this study lend further credence to the notion that EGCG and other flavonoids, such as luteolin, are 'multipotent therapeutic agents' that not only reduce toxic levels of brain Aß, but also hold the potential to protect neuronal mitochondrial function in AD.

Mitochondrial amyloid-beta levels are associated with the extent of mitochondrial dysfunction in different brain regions and the degree of cognitive impairment in Alzheimer's transgenic mice.

Mitochondrial dysfunction is observed in Alzheimer's disease (AD) brain, and the amyloid-beta (Abeta) peptide is known to induce mitochondrial dysfunction. The relative degree of mitochondrial dysfunction in different regions of the brain in AD is not completely understood. Moreover, the relationship between levels of synaptic mitochondrial Abeta and mitochondrial dysfunction has not been clearly established. Therefore synaptic and nonsynaptic mitochondria were isolated from the hippocampus, cortex, striatum, and amygdala of 12 month AbetaPPsw and AbetaPP+PS1 mouse models of AD as well as nontransgenic mice. Mitochondrial respiratory rates, reactive oxygen species production, membrane potential, and cytochrome c oxidase activity were measured. Hippocampal and cortical mitochondria showed the highest levels of mitochondrial dysfunction, while striatal mitochondria were moderately affected, and amygdalar mitochondria were minimally affected. Mitochondria from AbetaPP/PS1 brain regions were more impaired than those from AbetaPP mice. Mitochondrial Abeta levels nearly mirrored the extent of mitochondrial dysfunction. Synaptic mitochondria were more impaired than nonsynaptic mitochondria in the AD mouse models. The AbetaPP/PS1 mice showed more impairment in the cognitive interference task of working memory than the AbetaPP mice. The association between mitochondrial Abeta levels and mitochondrial dysfunction in mouse models of AD supports a primary role for mitochondrial Abeta in AD pathology. Moreover, the degree of cognitive impairment in AD transgenic mice can be linked to the extent of synaptic mitochondrial dysfunction and mitochondrial Abeta levels, suggesting that a mitochondrial Abeta-induced signaling cascade may contribute to cognitive impairment. Therapeutics that target this cascade could be beneficial in the treatment of AD.

Signaling properties of stratum oriens interneurons in the hippocampus of transgenic mice expressing EGFP in a subset of somatostatin-containing cells.

GABAergic interneurons constitute a heterogeneous group of cells that exert a powerful control on network excitability and are responsible for the oscillatory behavior crucial for information processing in the brain. These cells have been differently classified according to their morphological, neurochemical, and physiological characteristics. Here, whole cell patch clamp recordings were used to further characterize, in transgenic mice expressing EGFP in a subpopulation of GABAergic interneurons containing somatostatin (GIN mice), the functional properties of EGFP-positive cells in stratum oriens of the CA1 region of the hippocampus, in slice cultures obtained from P8 old animals. These cells showed passive and active membrane properties similar to those found in stratum oriens interneurons projecting to stratum lacunosum-moleculare. Moreover, they exhibited different firing patterns that were maintained upon membrane depolarization: irregular (48%), regular (30%), and clustered (22%). Trains of action potentials in interneurons evoked in a minority of principal cells (3/45) small amplitude GABAergic currents that at 20 Hz underwent short-term depression. In contrast, excitatory connections between principal cells and EGFP-positive interneurons were highly reliable (17/55) and exhibited a frequency and use-dependent facilitation particularly in the gamma band. In addition, recordings from paired of interconnected EGFP-positive cells revealed in 47% of the cases electrical coupling, which was abolished by carbenoxolone (200 microM). On average, the coupling coefficient was 0.21 +/- 0.07. When electrical coupling was particularly strong it acted as a powerful low-pass filter, thus contributing to alter the output of individual cells. In conclusion, it appears that the dynamic interaction between cells with various firing patterns could differently affect GABAergic signaling, leading, as suggested by simulation data, to a wide range of interneuronal communication within the hippocampal network.

Inflammation induces mitochondrial dysfunction and dopaminergic neurodegeneration in the nigrostriatal system.

Evidence suggests that chronic inflammation, mitochondrial dysfunction, and oxidative stress play significant and perhaps synergistic roles in Parkinson's disease (PD), where the primary pathology is significant loss of the dopaminergic neurons in the substantia nigra. The use of anti-inflammatory drugs for PD treatment has been proposed, and inhibition of cyclo-oxygenase-2 (COX-2) or activation of peroxisome proliferator-activated receptor gamma (PPAR-gamma) yields neuroprotection in MPTP-induced PD. Lipopolysaccharide (LPS) induces inflammation-driven dopaminergic neurodegeneration. We tested the hypothesis that celecoxib (Celebrex, COX-2 inhibitor) or pioglitazone (Actos, PPAR-gamma agonist) will reduce the LPS-induced inflammatory response, spare mitochondrial bioenergetics, and improve nigral dopaminergic neuronal survival. Rats were treated with vehicle, celecoxib, or pioglitazone and were intrastriatally injected with LPS. Inflammation, mitochondrial dysfunction, oxidative stress, decreased dopamine, and nigral dopaminergic neuronal loss were observed post-LPS. Celecoxib and pioglitazone provided neuroprotective properties by decreasing inflammation and restoring mitochondrial function. Pioglitazone also attenuated oxidative stress and partially restored striatal dopamine as well as demonstrated dopaminergic neuroprotection and reduced nigral microglial activation. In summary, intrastriatal LPS served as a model for inflammation-induced dopaminergic neurodegeneration, anti-inflammatory drugs provided protective properties, and pioglitazone or celecoxib may have therapeutic potential for the treatment of neuro-inflammation and PD.

Proteasome inhibition alters neural mitochondrial homeostasis and mitochondria turnover.

Inhibition of proteasome activity occurs in normal aging and in a wide variety of neurodegenerative conditions including Alzheimer's disease and Parkinson's disease. Although each of these conditions is also associated with mitochondrial dysfunction potentially mediated by proteasome inhibition, the relationship between proteasome inhibition and the loss of mitochondrial homeostasis in each of these conditions has not been fully elucidated. In this study, we conducted experimentation in order to begin to develop a more complete understanding of the effects proteasome inhibition has on neural mitochondrial homeostasis. Mitochondria within neural SH-SY5Y cells exposed to low level proteasome inhibition possessed similar morphological features and similar rates of electron transport chain activity under basal conditions as compared with untreated neural cultures of equal passage number. Despite such similarities, maximal complex I and complex II activities were dramatically reduced in neural cells subject to proteasome inhibition. Proteasome inhibition also increased mitochondrial reactive oxygen species production, reduced intramitochondrial protein translation, and increased cellular dependence on glycolysis. Finally, whereas proteasome inhibition generated cells that consistently possessed mitochondria located in close proximity to lysosomes with mitochondria present in the cellular debris located within autophagosomes, increased levels of lipofuscin suggest that impairments in mitochondrial turnover may occur following proteasome inhibition. Taken together, these data demonstrate that proteasome inhibition dramatically alters specific aspects of neural mitochondrial homeostasis and alters lysosomal-mediated degradation of mitochondria with both of these alterations potentially contributing to aging and age-related disease in the nervous system.