Space-Like Irradiation Exacerbated Cognitive Deficits and Amyloid Pathology in CRND8 Mouse Model of Alzheimer's Disease.

Background: Space radiation was linked to neurological damage and behavioral deficits which raised concerns of increased degenerative risk on the brain and development of Alzheimer's disease following space travel.

Objective: In this study, we investigated the effects of irradiation by 56Fe and 28Si in CRND8 mice, an Alzheimer's disease mouse model.

Methods: Six-month-old CRND8 mice were exposed to whole body irradiation by 56Fe and 28Si at 0.

Generation of Glioblastoma Patient-Derived Intracranial Xenografts for Preclinical Studies.

Glioblastoma multiforme (GBM) is the most malignant primary brain cancer affecting adults. Therapeutic options for GBM have remained the same for over a decade with no significant improvement. Many therapies that are successful in culture have failed in patients, likely due to the complex microenvironment in the brain, which has yet to be reproduced in any culture model.

Proteins inform survival-based differences in patients with glioblastoma.

Background: Improving the care of patients with glioblastoma (GB) requires accurate and reliable predictors of patient prognosis. Unfortunately, while protein markers are an effective readout of cellular function, proteomics has been underutilized in GB prognostic marker discovery.

Methods: For this study, GB patients were prospectively recruited and proteomics discovery using liquid chromatography-mass spectrometry analysis (LC-MS/MS) was performed for 27 patients including 13 short-term survivors (STS) (≤10 months) and 14 long-term survivors (LTS) (≥18 months).

Plant Virus-Like Particle In Situ Vaccine for Intracranial Glioma Immunotherapy.

Despite aggressive multi-modality treatment with surgery, radiation and chemotherapies, malignant glioma inevitably recurs and has dismal survival rates. Recent progress in immunotherapy has led to a resurgence of interest, and immunotherapies are being investigated for treatment of glioma. However, the unique brain anatomy and a highly immunosuppressive glioma microenvironment pose significant challenges to achieving efficacy.

Hydroxynonenal-generated crosslinking fluorophore accumulation in Alzheimer disease reveals a dichotomy of protein turnover.

Lipid peroxidation generates reactive aldehydes, most notably hydroxynonenal (HNE), which covalently bind amino acid residue side chains leading to protein inactivation and insolubility. Specific adducts of lipid peroxidation have been demonstrated in intimate association with the pathological lesions of Alzheimer disease (AD), suggesting that oxidative stress is a major component of AD pathogenesis. Some HNE-protein products result in protein crosslinking through a fluorescent compound similar to lipofuscin, linking lipid peroxidation and the lipofuscin accumulation that commonly occurs in post-mitotic cells such as neurons.

CD3 in Lewy pathology: does the abnormal recall of neurodevelopmental processes underlie Parkinson's disease.

CD3ζ is a subunit of the CD3 molecule that, until recently, appeared restricted to T cells and natural killer cells. However, experimental studies have demonstrated a role of CD3ζ in dendritic outgrowth in the visual system as well as in synaptic plasticity. Given the increasing evidence for uncharacteristic recapitulation of neurodevelopmental processes in neurodegenerative diseases, in this study, we evaluated brains from subjects with Parkinson's disease and Lewy body dementia for evidence of aberrant CD3 expression.

Lipoic acid and N-acetyl cysteine decrease mitochondrial-related oxidative stress in Alzheimer disease patient fibroblasts.

In this study, we evaluated the effect of lipoic acid (LA) and N-acetyl cysteine (NAC) on oxidative [4-hydroxy-2-nonenal, N(epsilon)-(carboxymethyl)lysine and heme oxygenase-1] and apoptotic (caspase 9 and Bax) markers in fibroblasts from patients with Alzheimer disease (AD) and age-matched and young controls. AD fibroblasts showed the highest levels of oxidative stress, and the antioxidants, lipoic acid (1 mM) and/or N-acetyl cysteine (100 microM) exerted a protective effect as evidenced by decreases in oxidative stress and apoptotic markers. Furthermore, we observed that the protective effect of LA and NAC was more pronounced when both agents were present simultaneously.

Cerebrotendinous xanthomatosis: case report with evidence of oxidative stress.

Cerebrotendinous xanthomatosis is an autosomal recessive disorder of bile acid synthesis, characterized by mutation in the mitochondrial enzyme 27-hydroxylase that leads to an accumulation of cholestanol and cholesterol. Characterized clinically by premature bilateral cataracts, slowly progressive neurological deterioration with dementia, cerebellar and brainstem signs, peripheral neuropathy, and seizures, the disease presents pathologically with lipid granulomata with foamy histiocytes and cholesterol clefts. Replacement therapy with chenodeoxycholic acid slows progression of the disease but does not reverse neurological deficits.

Vascular oxidative stress in Alzheimer disease.

Alzheimer disease and cerebrovascular dementia are two common causes of dementia and, by present diagnostic criteria, are mutually exclusive using vascular pathology as an arbitrary demarcation in differential diagnosis. However, evidence from epidemiological, neuropathological, clinical, pharmacological, and functional studies suggest considerable overlap in risk factors and pathological changes suggesting shared common pathogenic mechanisms between these two diseases such that vascular factors play a vital role in the pathogenesis of Alzheimer disease. A high energy demand and lack of an endogenous fuel reserve make the brain highly dependent upon a continuous blood supply where disruption of cerebral blood vessels and blood flow can have serious consequences on neural activities.

Increased expression of the remodeling- and tumorigenic-associated factor osteopontin in pyramidal neurons of the Alzheimer's disease brain.

Osteopontin (OPN) is a glycophosphoprotein expressed by several cell types and has pro-adhesive, chemotactic, and cytokine-like properties. OPN is involved in a number of physiologic and pathologic events including angiogenesis, apoptosis, inflammation, oxidative stress, remyelination, wound healing, bone remodeling, cell migration and tumorigenesis. Since these functions of OPN, and the events that it regulates, are involved with neurodegeneration, we examined whether OPN was differentially expressed in the hippocampus of the Alzheimer's disease (AD) compared with age-matched (59-93 years) control brain.

Steroidogenic acute regulatory protein (StAR): evidence of gonadotropin-induced steroidogenesis in Alzheimer disease.

Background: Alzheimer disease (AD) is clinically characterized by progressive memory loss, impairments in behavior, language and visual-spatial skills and ultimately, death. Epidemiological data reporting the predisposition of women to AD has led to a number of lines of evidence suggesting that age-related changes in hormones of the hypothalamic-pituitary-gonadal (HPG) axis following reproductive senescence, may contribute to the etiology of AD. Recent studies from our group and others have reported not only increases in circulating gonadotropins, namely luteinizing hormone (LH) in individuals with AD compared with control individuals, but also significant elevations of LH in vulnerable neuronal populations in individuals with AD compared to control cases as well as the highest density of gonadotropin receptors in the brain are found within the hippocampus, a region devastated in AD.

Nanoparticle iron chelators: a new therapeutic approach in Alzheimer disease and other neurologic disorders associated with trace metal imbalance.

Accumulating evidence suggests that oxidative stress may be a major etiologic factor in initiating and promoting neurodegeneration in Alzheimer disease. Contributing to this, there is a dyshomeostasis of metal ions in Alzheimer disease with abnormally high levels of redox-active metals, particularly iron, in affected areas of the brain. Although it is unclear whether metal excesses are the sole cause of oxidative stress and neurodegeneration or a by-product of neuronal loss, the finding that metal chelators can partially solubilize amyloid-beta deposits in Alzheimer disease suggests a promising therapeutic role for chelating agents.

Telomeres and telomerase in Alzheimer's disease: epiphenomena or a new focus for therapeutic strategy?

New approaches to the elucidation of Alzheimer disease, even those with solid data, are often ignored or dismissed as epiphenomenal when they differ from the mainstream or theoretical expectations. Here we present a new piece to the puzzle, decreases in telomere length, and telomerase expression in neuronal populations known to be vulnerable to degeneration and death in Alzheimer's disease. We can present the answers to the question "what," but the "why," "when," and "how" are not so easily answered.

Sequestration of p27 within the cytoplasm of cardiac myocytes in chronic ischemic heart disease: pathogenic implications for ischemic cardiomyopathy.

A number of recent studies have suggested that cardiac myocytes, previously considered post-mitotic, re-enter the cell cycle and possess the ability to proliferate with certain pathogenic stimuli. To study this further, we examined cellular proliferation in myocardial tissue from subjects with chronic ischemic heart disease-associated myocardial infarction and subsequent congestive heart failure. We found striking increases in cytoplasmic phospho-p27, a well-known mitotic regulator, compared to controls by both immunocytochemical and immunoblot analyses.

Alzheimer-specific epitopes of tau represent lipid peroxidation-induced conformations.

Several recent studies support a link between tau protein phosphorylation and adduction of tau by reactive carbonyls. Indeed, the phosphorylation-dependent adduction of tau by carbonyl products resulting from lipid peroxidation creates the neurofibrillary tangle-related antigen, Alz50. To determine whether epitopes of carbonyl-modified tau are major conformational changes associated with neurofibrillary tangle formation, we examined seven distinct antibodies raised against neurofibrillary tangles that recognize unique epitopes of tau in Alzheimer disease.

Tau modifiers as therapeutic targets for Alzheimer's disease.

Fibrillogenesis is a major feature of Alzheimer's disease (AD) and other neurodegenerative diseases. Fibers are correlated with disease severity and they have been implicated as playing a direct role in disease pathophysiology. In studies of tau, instead of finding causality with tau fibrils, we found that tau is associated with reduction of oxidative stress.

In situ localization of nonenzymatic peroxidase-like activity of tissue-bound transition metals.

Abnormalities in redox and/or transition metal homeostasis is characteristic of many pathological states. Here, we present protocols that can be used for the detection of both transition metals and redox state.

Neuroprotective properties of Bcl-w in Alzheimer disease.

While there is a host of pro-apoptotic stimuli that target neurons in Alzheimer disease (AD), given the chronicity of the disease and the survival of many neurons, those neurons must either avoid or, at minimum, delay apoptotic death signaling. In this study, we investigated Bcl-w, a novel member of the Bcl-2 family that promotes cell survival. In AD, we found increased levels of Bcl-w associated with neurofibrillary pathology and punctate intracytoplasmic structures whereas, in marked contrast, there are only low diffuse levels of Bcl-w in the neuronal cytoplasm of age-matched control cases.

Elevated expression of a regulator of the G2/M phase of the cell cycle, neuronal CIP-1-associated regulator of cyclin B, in Alzheimer's disease.

Adult neurons are generally accepted to be in a quiescent, nonproliferative state. However, it is becoming increasingly apparent that, in Alzheimer's disease (AD), alterations in cell cycle machinery, suggesting an attempt to reenter cell cycle, relate temporally and topographically to degenerating neurons. These findings, together with the fact that neurons lack the necessary components for completion of mitosis, have led to the notion that an ill-regulated attempt to reenter the cell cycle is associated with disease pathogenesis and, ultimately, neuronal degeneration.

Oxidative damage in cultured human olfactory neurons from Alzheimer's disease patients.

Oxidative abnormalities precede clinical and pathological manifestations of Alzheimer's disease and are the earliest pathological changes reported in the disease. The olfactory pathways and mucosa also display the pathological features associated with Alzheimer's disease in the brain. Olfactory neurons are unique because they can undergo neurogenesis and are able to be readily maintained in cell culture.

A metabolic basis for Alzheimer disease.

Most studies of Alzheimer's disease (AD) have focused on a single precipitating alteration as the etiological event rather than global changes closely linked to aging. Recent evidence suggests that the most significant of these global changes are metabolic. Here we present data indicating that metabolic rate, nutrition, and neuronal size are all early indicators of AD.

Oxidative damage in the olfactory system in Alzheimer's disease.

Increased oxidative damage is a prominent and early feature of vulnerable neurons in Alzheimer's disease (AD). However, while damage to proteins, sugars, lipids, nucleic acids and organelles such as lysosomes, mitochondria, and endoplasmic reticulum are evident, the source of increased reactive oxygen species has not been determined. Furthermore, a major limitation in further determining the source, as well as finding a means to arrest damage, is the paucity of cellular models directly homologous to AD since the vulnerable neurons of the brain in AD cannot be studied in vitro.

Increased p27, an essential component of cell cycle control, in Alzheimer's disease.

A number of recent findings have demonstrated re-expression of cell cycle-related proteins in vulnerable neurones in Alzheimer's disease. We hypothesize that this attempt by neurones to re-enter mitosis is a response to external growth stimuli that leads to an abortive re-entry into the cell cycle and, ultimately, neuronal degeneration. In this study, to further delineate the role of mitotic processes in the pathogenesis of Alzheimer's disease, we investigated p27, a cyclin-dependent kinase inhibitor that plays a negatively regulatory role in cell cycle progression that, once phosphorylated at Thr187, is degraded via an ubiquitin-proteasome pathway.

Adventiously-bound redox active iron and copper are at the center of oxidative damage in Alzheimer disease.

Central to oxidative damage in Alzheimer disease is the production of metal-catalyzed hydroxyl radicals that damage every category of macromolecule. Studies on redox-competent copper and iron indicate that redox activity in Alzheimer disease resides exclusively within the cytosol of vulnerable neurons and that chelation with deferoxamine or DTPA removes this activity. We have also found that while proteins that accumulate in Alzheimer disease such as tau, amyloid beta, and apolipoprotein E possess metal-binding sites, metal-associated cellular redox activity is more dependent on metal-nucleic acid binding.

Elevated luteinizing hormone expression colocalizes with neurons vulnerable to Alzheimer's disease pathology.

In individuals with Alzheimer's disease (AD), there is a two-fold elevation in the serum concentrations of the gonadotropins, luteinizing hormone (LH), and follicle stimulating hormone compared to age-matched controls. Whether this plays a role in disease pathogenesis is unclear. Nonetheless, gonadotropins are known to cross the blood brain barrier and the highest density of gonadotropin receptors in the brain are found within the hippocampus.