Alzheimer Disease: US Pacific Zone

Zhongling Feng, Gang Zhao, Lei Yu. · Bio Group, Nitto Denko Technical Corporation, Oceanside, California 92058, USA. · Am J Alzheimers Dis Other Demen. · Pubmed #19116300 No free full text.

Abstract: Alzheimer's disease is characterized by degeneration and dysfunction of synapses and neurons in brain regions critical for learning and memory functions. The endogenous generation of new neurons in certain regions of the mature brain, derived from primitive cells termed neural stem cells, has raised hope that neural stem cells may be recruited for structural brain repair. Stem cell therapy has been suggested as a possible strategy for replacing damaged circuitry and restoring learning and memory abilities in patients with Alzheimer's disease. In this review, we outline the promising investigations that are raising hope, and understanding the challenges behind translating underlying stem cell biology into novel clinical therapeutic potential in Alzheimer's disease.

Cotman CW, Head E. · Institute for Brain Aging & Dementia, Department of Neurology, University of California, Irvine, CA 92697-4540, USA. · J Alzheimers Dis. · Pubmed #19096165 No free full text.

Abstract: Aged dogs (beagles) develop losses in executive function, learning and memory. The severity of decline in these cognitive domains represents a spectrum that captures normal aging, mild cognitive impairment and early/mild Alzheimer's disease (AD) in humans. In parallel, dogs naturally accumulate several types of neuropathology (although not all) consistent with human brain aging and AD including cortical atrophy, neuron loss, loss of neurogenesis, amyloid-beta (Abeta) plaques, cerebral amyloid angiopathy and oxidative damage. Many of these neuropathological features correlate with the extent of cognitive decline in a brain region-dependent manner. Dogs are ideally suited for longitudinal studies, and we provide a summary of the beneficial effects of an antioxidant diet, behavioral enrichment, and Abeta immunotherapy. In addition, combinatorial treatment approaches can be a powerful strategy for improving brain function through enhancement of multiple molecular pathways.

Sparks DL. · Roberts Laboratory for Neurodegenerative Disease Research, Sun Health Research Institute, Sun City, AZ 85351, USA. · J Alzheimers Dis. · Pubmed #19096162 No free full text.

Abstract: Pioneering autopsy studies revealed a possible link between coronary artery disease, cholesterol and Alzheimer's disease (AD). In the cholesterol-fed rabbit model of human coronary artery disease, we identified numerous neuropathologic features of AD including central accumulation of amyloid-beta (Abeta) and cognitive deficits compared to rabbits fed unaltered diet. Removing cholesterol from the diet or treatment with cholesterol-lowering medications reversed the severity of AD-like alterations. This fostered the rationale for testing a cholesterol-lowering statin medication for benefit in the treatment of AD. Further studies suggested that the cholesterol-fed rabbit was a viable model for AD, but the severity of the neuropathology produced exhibited gender-related differences. Furthermore the induction of AD-like neuropathology by dietary cholesterol was found to depend on the quality of water the animal was drinking. Cholesterol-fed rabbits drinking distilled water showed minimal central changes, whereas animals drinking distilled water supplemented with low levels of copper were severely affected. It was clear that cholesterol caused the over-production of Abeta in the brain and copper influenced its clearance to the blood. Emerging data suggest that low-density lipoprotein receptor-related protein-1 (LRP) on brain capillaries clears Abeta from brain and that excess circulating copper negatively influences this process.

Costantino HR, Leonard AK, Brandt G, Johnson PH, Quay SC. · Nastech Pharmaceutical Company Inc, 3830 Monte Villa Parkway, Bothell, WA 98021, USA. · BMC Neurosci. · Pubmed #19091003 links to  free full text

Abstract: This short review outlines the rationale, challenges, and opportunities for intranasal acetylcholinesterases, in particular galantamine. An in vitro screening model facilitated the development of a therapeutically viable formulation. In vivo testing confirmed achievement of therapeutically relevant drug levels that matched or exceeded those for oral dosing, with a dramatic reduction in undesired emetic responses. Intranasal drug delivery is an effective option for the treatment of Alzheimer's disease and other central nervous system disorders.

Cashman JR, Ghirmai S, Abel KJ, Fiala M. · Human BioMolecular Research Institute, San Diego, CA 92121, USA. · BMC Neurosci. · Pubmed #19090986 links to  free full text

Abstract: Alzheimer's disease (AD) is a neurodegenerative disease characterized by the accumulation of intracellular and extracellular aggregates. According to the amyloid beta (Abeta) hypothesis, amyloidosis occurring in the brain is a leading cause of neurodegeneration in AD. Defects in the innate immune system may decrease the clearance of Abeta in the brain. Macrophages of most AD patients do not transport Abeta into endosomes and lysosomes, and monocytes from AD patients do not efficiently clear Abeta from AD brain. After stimulation with Abeta, mononuclear cells of normal subjects display up-regulated transcription of MGAT3, which encodes beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase, and Toll-like receptor (TLR) genes. Monocytes of AD patients generally down-regulate these genes. A commonly used, naturally occurring material from a spice that enhances certain key functions defective in cells of innate immunity of many AD patients has shown epidemiologic rationale for use in AD treatment. Bisdemethoxycurcumin, a natural curcumin, is a minor constituent of turmeric (curry), and it enhances phagocytosis and clearance of Abeta in cells from most AD patients. We confirmed the effectiveness of a synthetic version of the same compound. In mononuclear cells of most AD patients, bisdemethoxycurcumin enhanced defective phagocytosis of Abeta and increased the transcription of MGAT3 and TLR genes. The potency of bisdemethoxycurcumin as a highly purified compound in facilitating the clearance of Abeta in mononuclear cells suggests the promise of enhanced effectiveness compared to curcuminoid mixtures. Bisdemethoxycurcumin appears to enhance immune function in mononuclear cells of AD patients and may provide a novel approach to AD immunotherapy.

Webster NJ, Pirrung MC. · Veterans Medical Research Foundation and VA San Diego Healthcare System, San Diego, CA 92161, USA. · BMC Neurosci. · Pubmed #19090982 links to  free full text

Abstract: The neurotrophin signaling network is critical to the development and survival of many neuronal populations. Especially sensitive to imbalances in the neurotrophin system, cholinergic neurons in the basal forebrain are progressively lost in Alzheimer's disease. Therapeutic use of neurotrophins to prevent this loss is hampered, however, by a number of pharmacological challenges. These include a lack of transport across the blood-brain barrier, rapid degradation in the circulation, and difficulty in production. In this review we discuss the evidence supporting the neurotrophin system's role in preventing neurodegeneration and survey some of the pharmacological strategies being pursued to develop effective therapeutics targeting neurotrophin function.

Yamin G, Ono K, Inayathullah M, Teplow DB. · Department of Neurology, David Geffen School of Medicine at UCLA, 635 Charles E. Young Drive South (Room 445), Los Angeles, California 90095, USA. · Curr Pharm Des. · Pubmed #19075703 No free full text.

Abstract: Alzheimer's disease (AD), the most common neurodegenerative disorder in the aged, is characterized by the cerebral deposition of fibrils formed by the amyloid beta-protein (Abeta), a 40-42 amino acid peptide. The folding of Abeta into neurotoxic oligomeric, protofibrillar, and fibrillar assemblies is hypothesized to be the key pathologic event in AD. Abeta is formed through cleavage of the Abeta precursor protein by two endoproteinases, beta-secretase and gamma-secretase, that cleave the Abeta N-terminus and C-terminus, respectively. These facts support the relevance of therapeutic strategies targeting Abeta production, assembly, clearance, and neurotoxicity. Currently, no disease-modifying therapeutic agents are available for AD patients. Instead, existing therapeutics provide only modest symptomatic benefits for a limited time. We summarize here recent efforts to produce therapeutic drugs targeting Abeta assembly. A number of approaches are being used in these efforts, including immunological, nutraceutical, and more classical medicinal chemical (peptidic inhibitors, carbohydrate-containing compounds, polyamines, "drug-like" compounds, chaperones, metal chelators, and osmolytes), and many of these have progressed to phase III clinical trails. We also discuss briefly a number of less mature, but intriguing, strategies that have therapeutic potential. Although initial trials of some disease-modifying agents have failed, we argue that substantial cause for optimism exists.

Britschgi M, Wyss-Coray T. · Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305-5235, USA. · Arch Neurol. · Pubmed #19064741 No free full text.

Abstract: Alzheimer disease (AD) has become one of the main health concerns for the elderly population in the United States. Current treatments target symptoms only, but several advanced clinical trials are testing new drugs that are potentially disease modifying. Because AD is still difficult to diagnose in its earliest stages and the disease process is estimated to start many years before current clinical diagnosis is made, accurate and simple diagnostic tools are urgently needed. We recently described a blood-based panel of secreted signaling proteins that distinguishes between blinded samples from patients with AD and control subjects with high accuracy. The same proteins also predicted progression to AD in preclinical patients with mild cognitive impairment several years before clinical diagnosis for AD was made. Herein, we describe these findings and discuss the potential for a more general application of our proteomic approach in understanding and diagnosing disease.

Murphy C. · Department of Psychology, San Diego State University, 6363 Alvarado Court, San Diego, CA 92120, USA. · J Nutr Elder. · Pubmed #19042574 No free full text.

Abstract: Taste and smell are critical to dietary selection, especially for older adults, whose appetite is reduced. Neuroimaging studies can elucidate the process that causes the decrease of chemosensory functions with aging. The profound lost of olfactory functions in persons with Alzheimer disease accentuate the problem of inadequate food intake and disease progression.

Tobinick E. · Institute for Neurological Research, a private medical group, inc. 100 UCLA Medical Plaza, Suites 205-210, Los Angeles, CA 90095, United States. · Drug Discov Today. · Pubmed #19027875 No free full text.

Abstract: Excess TNF is centrally involved in the pathogenesis of a variety of neuroinflammatory disorders, including Alzheimer's disease, other forms of dementia, intervertebral disc-related pain, and related disorders. TNF causes neuronal dysfunction, regulates synaptic mechanisms, and mediates amyloid-induced disruption of molecular mechanisms involved in memory. Perispinal administration of etanercept, a potent anti-TNF fusion protein, is a treatment modality whose rapid clinical effects may be related to modulation of these TNF-related mechanisms, particularly the role of TNF as a gliotransmitter capable of regulating synaptic transmission. This approach utilizes therapeutic delivery of etanercept across the dura via the cerebrospinal venous system, a confluence of the venous plexuses of the spine and the brain, in which flow is bi-directional owing to the absence of venous valves.

Cherrier MM. · Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine and Veterans Administration Puget Sound Health Care System S-182 GRECC, Seattle, WA 98108, USA. · Front Horm Res. · Pubmed #19011295 No free full text.

Abstract: Low testosterone is associated with many physical complaints as well as cognitive complaints. This article reviews the neurobiologic connection between gonadal steroids and cognitive functions, and mechanisms by which T may be considered neuroprotective. Studies of hormone replacement therapy in hypogonadal men as well as older men with late-onset hypogonadism (LOH) are reviewed as well as epidemiological studies of endogenous hormones and cognition. Studies examining T treatment in men with memory disorders such as Alzheimer's disease (AD) will also be reviewed. Some but not all studies of androgen replacement therapy in hypogonadal younger men, older men with LOH and AD patients suggest a potential beneficial effect on cognition, however a recent study indicated a negative effect. Most studies to date have been small and need further replication with randomized controlled studies using larger sample sizes with specific consideration of treatment risk factors.

Steinman L. · Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA. · J Clin Invest. · Pubmed #18982162 links to  free full text

Abstract: The three most prevalent human disorders of the CNS in which immunity and inflammation are likely to have vital roles (excluding infection of the CNS) are fever, multiple sclerosis (MS), and Alzheimer disease (AD). As reviewed here, cytokines are critical in the induction of fever, the pathogenesis of MS, and the pathobiology of AD. Indeed, antibodies targeting cytokines have been used as a therapy for individuals with unusual and persistent febrile reactions not responsive to common antipyretics, while a recombinant cytokine is the most popular treatment for the relapsing-remitting form of MS. Although cytokine-modulating therapies are not currently in clinical use for the treatment of AD, cytokines can ameliorate disease pathology in certain experimental models of AD, suggesting a potential for future therapeutic opportunities.

Hook V, Schechter I, Demuth HU, Hook G. · Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093, USA. · Biol Chem. · Pubmed #18979625 links to  free full text

Abstract: This highlight article describes three Alzheimer's disease (AD) studies presented at the 5th General Meeting of the International Proteolysis Society that address enzymatic mechanisms for producing neurotoxic beta-amyloid (Abeta) peptides. One group described the poor kinetics of BACE 1 for cleaving the wild-type (WT) beta-secretase site of APP found in most AD patients. They showed that cathepsin D displays BACE 1-like specificity and cathepsin D is 280-fold more abundant in human brain than BACE 1. Nevertheless, as BACE 1 and cathepsin D show poor activity towards the WT beta-secretase site, they suggested continuing the search for additional beta-secretase(s). The second group reported cathepsin B as an alternative beta-secretase possessing excellent kinetic efficiency and specificity for the WT beta-secretase site. Significantly, inhibitors of cathepsin B improved memory, with reduced amyloid plaques and decreased Abeta(40/42) in brains of AD animal models expressing amyloid precursor protein containing the WT beta-secretase site. The third group addressed isoaspartate and pyroglutamate (pGlu) posttranslational modifications of Abeta. Results showed that cathepsin B, but not BACE 1, efficiently cleaves the WT beta-secretase isoaspartate site. Furthermore, cyclization of N-terminal Glu by glutaminyl cyclase generates highly amyloidogenic pGluAbeta(3-40/42). These presentations suggest cathepsin B and glutaminyl cyclase as potential new AD therapeutic targets.

Askanas V, Engel WK. · Department of Neurology, USC Neuromuscular Center, Good Samaritan Hospital, University of Southern California Keck School of Medicine, 637 South Lucas Avenue, Los Angeles, CA 90017-1912, USA. · Acta Neuropathol. · Pubmed #18974994 No free full text.

Abstract: Sporadic inclusion-body myositis (s-IBM), the most common muscle disease of older persons, is of unknown cause and lacks successful treatment. Here we summarize diagnostic criteria and discuss our current understanding of the steps in the pathogenic cascade. While it is agreed that both degeneration and mononuclear-cell inflammation are components of the s-IBM pathology, how each relates to the pathogenesis remains unsettled. We suggest that the intra-muscle-fiber degenerative component plays the primary role, leading to muscle-fiber destruction and clinical weakness, since anti-inflammatory treatments are not of sustained benefit. We discuss possible treatment strategies aimed toward ameliorating a degenerative component, for example, lithium and resveratrol. Also discussed are the intriguing phenotypic similarities between s-IBM muscle fibers and the brains of Alzheimer and Parkinson's diseases, the most common neurodegenerative diseases associated with aging. Similarities include, in the respective tissues, cellular aging, mitochondrial abnormalities, oxidative and endoplasmic-reticulum stresses, proteasome inhibition and multiprotein aggregates.

Aisen PS. · Alzheimer's Disease Cooperative Study, University of California at San Diego, CA, USA. · CNS Spectr. · Pubmed #18955961 links to  free full text

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Cummings JL. · David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. · CNS Spectr. · Pubmed #18955958 links to  free full text

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Peskind ER. · Alzheimer's Disease Research Center, Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington, USA. · CNS Spectr. · Pubmed #18955957 links to  free full text

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Zhong N, Weisgraber KH. · Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA. · J Biol Chem. · Pubmed #18948255 No free full text.

Abstract: Despite intense interest, the molecular mechanisms underlying the association of apoE4 with Alzheimer disease are not clear. Because the function (or dysfunction) of a protein is based on its structure, this review focuses on the effects of the structural differences among the isoforms on neurodegeneration. Understanding how apoE4 structure impacts neurodegeneration is likely to provide mechanistic insight as well as potential therapeutic approaches to blunt or reduce its effects.

Morrissette DA, Parachikova A, Green KN, LaFerla FM. · Department of Neurobiology and Behavior and Institute for Brain Aging and Dementia, University of California, Irvine, California 92697-4545, USA. · J Biol Chem. · Pubmed #18948253 No free full text.

Abstract: During the past 2 decades, the elucidation of susceptibility and causative genes for Alzheimer disease as well as proteins involved in the pathogenic process has greatly facilitated the development of genetically altered mouse models. These models have played a major role in defining critical disease-related mechanisms and in evaluating novel therapeutic approaches, with many treatments currently in clinical trial owing their origins to studies initially performed in mice. This review discusses the utility of transgenic mice as a research tool and their contributions to our understanding of Alzheimer disease.

Cummings JL. · Departments of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. · Int Rev Psychiatry. · Pubmed #18925488 No free full text.

Abstract: Understanding of the pathophysiological basis of Alzheimer's disease (AD) is increasing rapidly and a variety of potential treatment modalities have emerged based on these improved mechanistic insights. The optimal way of proceeding with disease-modifying drug development remains to be clarified and controversies have emerged regarding the definition of Alzheimer's disease, the participation of mild cognitive impairment patients in clinical trials, the definition of disease modification, the potential impediments to satisfaction from patients receiving disease-modifying therapy, the importance of add-on therapy with symptomatic agents, the optimal clinical trial design to demonstrate disease modification, the best means of minimizing time spent in Phase II of drug development, the potential role of adaptive designs in clinical trials, the use of enrichment designs in clinical trials, the role of biomarkers in clinical trials, the treatment of advanced patients with disease-modifying agents, and distinctions between disease modification and disease prevention. The questions surrounding these issues must be resolved as disease-modifying therapies for AD are advanced. These controversies are framed and potential directions towards resolution described.

Roychaudhuri R, Yang M, Hoshi MM, Teplow DB. · Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA. · J Biol Chem. · Pubmed #18845536 No free full text.

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Lu B, Vogel H. · Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. · Annu Rev Pathol. · Pubmed #18842101 No free full text.

Abstract: Neurodegenerative diseases are progressive disorders of the nervous system that affect specific cellular populations in the central and peripheral nervous systems. Although most cases are sporadic, genes associated with familial cases have been identified, thus enabling the development of animal models. Invertebrates such as Drosophila have recently emerged as model systems for studying mechanisms of neurodegeneration in several major neurodegenerative diseases. These models are also excellent in vivo systems for the testing of therapeutic compounds. Genetic studies using these animal models have provided novel insights into the disease process. We anticipate that further exploration of the animal models will further our understanding of mechanisms of neurodegeneration as well as facilitate the development of rational treatments for debilitating degenerative diseases.

Kheifets L, Bowman JD, Checkoway H, Feychting M, Harrington JM, Kavet R, Marsh G, Mezei G, Renew DC, van Wijngaarden E. · UCLA School of Public Health, Department of Epidemiology, 73-284 CHS, 650 Charles E Young Drive South, Los Angeles, CA 90095-1772, USA. · Occup Environ Med. · Pubmed #18805878 No free full text.

Abstract: The occupational epidemiological literature on extremely low frequency electric and magnetic fields (EMF) and health encompasses a large number of studies of varying design and quality that have addressed many health outcomes, including various cancers, cardiovascular disease, depression and suicide, and neurodegenerative diseases, such as Alzheimer disease and amyotrophic lateral sclerosis (ALS). At a 2006 workshop we reviewed studies of occupational EMF exposure with an emphasis on methodological weaknesses, and proposed analytical ways to address some of these. We also developed research priorities that we hope will address remaining uncertainties. Broadly speaking, extensive epidemiological research conducted during the past 20 years on occupational EMF exposure does not indicate strong or consistent associations with cancer or any other health outcomes. Inconsistent results for many of the outcomes may be attributable to numerous shortcomings in the studies, most notably in exposure assessment. There is, however, no obvious correlation between exposure assessment quality and observed associations. Nevertheless, for future research, the highest priorities emerge in both the areas of exposure assessment and investigation of ALS. To better assess exposure, we call for the development of a more complete job-exposure matrix that combines job title, work environment and task, and an index of exposure to electric fields, magnetic fields, spark discharge, contact current, and other chemical and physical agents. For ALS, we propose an international collaborative study capable of illuminating a reported association with electrical occupations by disentangling the potential roles of electric shocks, magnetic fields and bias. Such a study will potentially lead to evidence-based measures to protect public health.

Jacobson SA, Sabbagh MN. · Research Cleo Roberts Center for Clinical Research, Sun Health Research Institute, 10515 W Santa Fe Drive, Sun City, AZ 85351, USA. · Expert Opin Drug Metab Toxicol. · Pubmed #18798705 No free full text.

Abstract: BACKGROUND: There is substantial evidence from preclinical studies that cholinesterase inhibitors affect basic processes that have been implicated in Alzheimer's disease (AD) pathogenesis, suggesting that these drugs should have both disease-modifying and neuroprotective effects in humans. The evidence seems to be strongest in relation to donepezil, which is the focus of this review. OBJECTIVE: To summarize the preclinical literature regarding the effects of donepezil on cellular and molecular processes underlying AD. Second, to suggest reasons for the apparent disparity between robust preclinical effects and modest clinical effects of this drug and others in its class. METHODS: Articles retrieved from PubMed searches were critically reviewed and selected for relevance to the current topic. RESULTS/CONCLUSION: Donepezil has numerous cellular and molecular effects that should influence AD progression.

Chiang PK, Lam MA, Luo Y. · Pharmadyn Inc., 525 Del Rey Ave, Suite B, Sunnyvale, CA 94085-3528, USA. · Curr Mol Med. · Pubmed #18781964 No free full text.

Abstract: The 'amyloid cascade hypothesis' links amyloid beta peptide (Abeta) with the pathological process of Alzheimer's disease (AD) and it still awaits universal acceptance. Amyloid precursor protein (APP), through the actions of the gamma-secretase complex, eventually becomes a different Abetaspecies. The various Abeta species have proven to be difficult to investigate under physiological conditions, and the species of Abeta responsible for neurotoxicity has yet to be unequivocally identified. The two important Abeta peptides involved are Abeta(1-40) and Abeta(1-42), and each has been ascribed both toxic and beneficial attributes. The ratio between the two species can be important in AD etiology. Additionally, shorter variants of Abeta peptides such as Abeta(1-8), Abeta(9-16) and Abeta(16) have also been shown to be potential participants in AD pathology. Interestingly, a new 56-kDa Abeta peptide (Abeta*56) disrupts memory when injected into the brains of young rats. Transgenic mice models are complicated by the interplay between various human Abeta types and the mouse Abeta types in the mouse brains. However, the accumulation of Abeta(1-42) in the brains of transgenic C. elegans worms and Drosophila is indeed detrimental. A less investigated aspect of AD is epigenetics, but in time the investigation of the role of epigenetics in AD may add to our understanding of the development of AD.