Morphometric imaging biomarker identifies Alzheimer's disease even among mixed dementia patients.

A definitive diagnosis of Alzheimer's disease (AD), even in the presence of co-morbid neuropathology (occurring in > 50% of AD cases), is a significant unmet medical need that has obstructed the discovery of effective AD therapeutics. An AD-biomarker, the Morphometric Imaging (MI) assay on cultured skin fibroblasts, was used in a double-blind, allcomers (ages 55-90) trial of 3 patient cohorts: AD dementia patients, N = 25, all autopsy confirmed, non-AD dementia patients, N = 21-all autopsy or genetically confirmed; and non-demented control (AHC) patients N = 27. Fibroblasts cells isolated from 3-mm skin punch biopsies were cultured on a 3-D Matrigel matrix with movement dynamics quantified by image analysis.

Cytokines and Cytokine Receptors Involved in the Pathogenesis of Alzheimer's Disease.

Inflammatory mechanisms are implicated in the pathology of Alzheimer's disease (AD). However, it is unclear whether inflammatory alterations are a cause or consequence of neurodegeneration leading to dementia. Clarifying this issue would provide valuable insight into the early diagnosis and therapeutic management of AD.

Acute Motor-dominant Polyneuropathy as Guillain-Barré Syndrome and Multiple Mononeuropathies in a Patient with Sjögren's Syndrome.

A patient with xerostomia and xerophthalmia due to Sjögren's syndrome presented with acute motor-dominant polyneuropathy and multiple mononeuropathy with antiganglioside antibodies. Nerve conduction studies and a sural nerve biopsy revealed the neuropathy as a mixture of segmental demyelination and axonal degeneration. Positive results were obtained for several antiganglioside antibodies.

Alpha1-chimaerin, a Rac1 GTPase-activating protein, is expressed at reduced mRNA levels in the brain of Alzheimer's disease patients.

Alpha1-chimaerin is a GTPase-activating protein (GAP) for Rac1, a member of the Rho small GTPase family, whose action leads to the inactivation of Rac1. Rac1 activity is upregulated in Alzheimer's disease, but little is known about the role of α1-chimaerin. In this study, we investigated the expression and localization of α1-chimaerin mRNA in postmortem human brains from patients with Alzheimer's disease and control subjects.

Deficiency of GDNF Receptor GFRα1 in Alzheimer's Neurons Results in Neuronal Death.

We have recently developed aged cortical neuron cultures from autopsied human brains with Alzheimer's disease (AD). During the culturing process, we found that glutamatergic cortical neurons from the AD brain lacked a response to glial cell line-derived neurotrophic factor (GDNF), including no axonal regrowth, and were starting to undergo apoptosis. Here we showed that, in cortical neurons from age- and gender-matched cognitively normal control (NC) subjects (NC neurons), GDNF enhanced the expression of GDNF family receptor subtype α1 (GFRα1), but not the other three subtypes (GFRα2, GFRα3, and GFRα4), whereas GDNF failed to induce GFRα1 expression in cortical neurons from the AD brain (AD neurons).

Effluent syntaxin3 from dying cells affords protection against apoptosis in epidermal keratinocytes.

Ultra-violet B (UVB)-induced oxidative stress crucially perturbs the epidermal homeostasis, and the skin is endowed with protective mechanisms to take action against such damage. Here, we show the possible involvement of t-SNARE protein syntaxin3, a membrane fusion mediator of cytoplasmic vesicles, and which is released from dying keratinocytes, to play a role in this response. UVB irradiation, which generates reactive oxidative stress in cells, was shown to lead to the keratinocyte cell death accompanied by a release of cytoplasmic syntaxin3.

Reduction of β-amyloid accumulation by reticulon 3 in transgenic mice.

Inhibition of the β-secretase, BACE1, which cleaves amyloid precursor protein (APP) to produce β-amyloid protein (Aβ), is thought to be a feasible therapeutic strategy for Alzheimer's disease. Reticulon (RTN) proteins such as RTN3 have been identified as membrane proteins that interact with BACE1 and inhibit its Aβ-generating activity. In this study, we investigated whether RTN3 can regulate Aβ production in vivo, using transgenic (Tg) mice expressing APP with Swedish and London mutations (APP Tg mice) and those expressing RTN3; the latter mice showed ~1.

Expression and localization of mitochondrial ferritin mRNA in Alzheimer's disease cerebral cortex.

Mitochondrial ferritin (MtF) has been identified as a novel ferritin encoded by an intron-lacking gene with specific mitochondrial localization located on chromosome 5q23.1. MtF has been associated with neurodegenerative disorders such as Friedreich ataxia and restless leg syndrome.

Expression profiles of cytokines in the brains of Alzheimer's disease (AD) patients compared to the brains of non-demented patients with and without increasing AD pathology.

Neuroinflammation is involved in the pathology of Alzheimer's disease (AD). Our major focus was to clarify whether neuroinflammation plays an important role in AD pathogenesis, particularly prior to the manifestation of overt dementia. We analyzed cytokine expression profiles of the brain, with focus on non-demented patients with increasing AD pathology, referred to as high pathology control (HPC) patients, who provide an intermediate subset between AD and normal control subjects, referred to as low pathology control (LPC) patients.

Infiltration of T lymphocytes and expression of icam-1 in the hippocampus of patients with hippocampal sclerosis.

We and others have previously shown that reactive microglia express the major histocompatibility complex (MHC) class I and class II antigens in the hippocampus of patients suffering from epilepsy. Although the MHC glycoproteins serve as restriction elements for T lymphocytes, there is little information available regarding T lymphocytes in hippocampal sclerosis. In the present study, we investigated T lymphocyte infiltration in human hippocampi in four cases of epilepsy with hippocampal sclerosis, as well as in four control cases without neurological disease.

Expression and localization of lactotransferrin messenger RNA in the cortex of Alzheimer's disease.

We and others have previously reported that lactotransferrin (LF), acting both as an iron-binding protein and inflammatory modulator, is greatly up-regulated in the brain of patients with Alzheimer's disease (AD). However, it remains unknown which type of cells express LF in the brain of AD. In this study, therefore, we investigated the expression and localization of LF messenger RNA (mRNA) in the cerebral cortex of AD and control cases using real-time polymerase chain reaction (PCR) and in situ hybridization histochemistry.

Multiple cytokines are involved in the early events leading to the Alzheimer's disease pathology.

It is likely that neuroinflammation begins well before detectable cognitive impairment in Alzheimer's disease (AD) occurs. Clarifying the alterations occurring prior to the clinical manifestation of overt AD dementia may provide valuable insight into the early diagnosis and management of AD. Herein, to address the issue that neuroinflammation precedes development of AD pathology, we analyzed cytokine expression profiles of the brain, with focus on non-demented control patients with increasing AD pathology, referred to as high pathology control (HPC) cases, who provide an intermediate subset between AD and normal control cases referred to as low pathology control (LPC) cases.

Autopsy case of pure akinesia showing pallidonigro-luysian atrophy.

A 60-year-old man developed levodopa-resistant pure akinesia. The patient gradually became more akinetic without accompanying gaze palsies, nuchal dystonia, or other parkinsonian features such as rigidity or tremor. At the age of 71, he died of bronchopneumonia.

Immunohistochemical distribution of cation-dependent mannose 6-phosphate receptors in the mouse central nervous system: comparison with that of cation-independent mannose 6-phophate receptors.

Most mammalian cells express two types of mannose 6-phosphate (M6P) receptors (MPRs), which are involved in the sorting of lysosomal enzymes within the cells. They are referred to as cation-dependent (CD-) MPR and cation-independent (CI-) MPR/insulin-like growth factor II receptor (IGF-IIR), based on their divalent cation requirements and the ability to bind IGF-II. The complementary actions of these two related but distinct MPRs in the sorting function suggest that they have different immunohistochemical distributions.

Tumor necrosis factor death receptor signaling cascade is required for amyloid-beta protein-induced neuron death.

Tumor necrosis factor type I receptor (TNFRI), a death receptor, mediates apoptosis and plays a crucial role in the interaction between the nervous and immune systems. A direct link between death receptor activation and signal cascade-mediated neuron death in brains with neurodegenerative disorders remains inconclusive. Here, we show that amyloid-beta protein (Abeta), a major component of plaques in the Alzheimer's diseased brain, induces neuronal apoptosis through TNFRI by using primary neurons overexpressing TNFRI by viral infection or neurons from TNFRI knock-out mice.

The temporal localization of frame-shift ubiquitin-B and amyloid precursor protein, and complement proteins in the brain of non-demented control patients with increasing Alzheimer's disease pathology.

Transcriptional misreading of dinucleotide repeats that generates deletions in RNA and produces frame-shift proteins with loss of function has been reported in Alzheimer's disease (AD). Here frame-shift ubiquitin-B and amyloid precursor protein were immunochemically shown to exist in the brain of high pathology control (HPC) patients with AD pathology but without prior dementia. These proteins were absent in low pathology control patients with limited AD pathology and no dementia.

Isolation of living neurons from human elderly brains using the immunomagnetic sorting DNA-linker system.

Isolation and culture of mature neurons from affected brain regions during diseased states provide a well-suited in vitro model system to study age-related neurodegeneration under dynamic conditions at cellular levels. We have developed a novel technique to isolate living neurons from rapidly autopsied human elderly brains, and have succeeded in keeping them alive in vitro. Specifically, the parietal cortex blocks were fractionated by density gradients and further enriched for neurons by an immunomagnetic sorting DNA-linker technique.

Target depletion of distinct tumor necrosis factor receptor subtypes reveals hippocampal neuron death and survival through different signal transduction pathways.

Tumor necrosis factor receptor-I (TNFRI) and TNFRII are two TNFR subtypes in the immune system, but their roles in the brain remain unclear. Here we present a novel interaction between TNFR subtypes and TNF-alpha in the brain. Our studies on target-depleted TNFR in mice show that TNF-alpha has little effect on hippocampal neurons in which TNFRI, containing an "intracellular death domain," is absent (TNFRI -/-), whereas neurons from TNFRII knock-out mice are vulnerable to TNF-alpha even at low doses.

Suppressive effects of phosphodiesterase type IV inhibitors on rat cultured microglial cells: comparison with other types of cAMP-elevating agents.

We investigated the effects of inhibitors of cAMP-specific phosphodiesterase type IV (PDE IV) on cultured rat microglial cells. Microglial cells expressed mRNA encoding PDE IV. Rolipram and RO-20-1724, specific inhibitors of PDE IV, elevated the intracellular cAMP level much higher than the other types of PDE inhibitors.