Alzheimer Disease: California

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

This publication has no abstract.

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

This publication has no abstract.

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.

This publication has no abstract.

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.

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.

Arakawa T, Kita Y, Niikura T. · Alliance Protein Laboratories, Thousand Oaks, CA 91360, USA. · Curr Med Chem. · Pubmed #18781936 No free full text.

Abstract: Alzheimer's disease (AD) is a complex disease, involving multiple factors such as the production of aggregation-prone amyloid beta (Abeta) peptides, the formation of fibrillarly tangles of microtubule-associating proteins, Tau, and the polymorphism of cholesterol binding protein, APOE4. While understanding the mechanism of AD and the involvement of key players should lead to rational drug discovery against this disease, a traditional screening approach should also work for identifying drugs using AD models. We have used a cellular AD model, in which a cell death was induced by AD-causing neurotoxicities, and then screened the genes, which rescued the cells from the cell death. This resulted in isolation of a gene encoding a novel 24-amino acid long peptide, termed Humanin (HN), which protected neuronal cells at approximately microM level. Surprisingly, these gene products and the synthetic peptides not only protected neurons from cell death induced by Abeta-related neurotoxicities, but also Abeta-unrelated neurotoxicities. While a broad range of activities of HN against AD-related insults is discovered, the detailed mechanism of its action is still obscure. Structure analysis of HN showed that it is largely disordered and flexible at low peptide concentrations and heavily aggregates at high concentrations. Interestingly, one of the HN analogs, which is 10000-times more active than the parent HN molecule (i.e. active below nM range), was found to be monomeric. Based on findings of structural analyses, we propose here that membrane environment may enable HN to achieve high affinity for target protein(s) with multiple-transmembrane domains, such as G-protein coupled receptors.

Dhawan N, Puangco J, Jandial R. · UCLA Department of Medicine, CA, USA. · Neuro Endocrinol Lett. · Pubmed #18766151 No free full text.

Abstract: Alzheimer's disease (AD) is a serious neurodegenerative disease of aging. Recent projections of the dramatic increase in AD incidence worldwide by 2050 reveal its magnitude as a world-wide health crisis and underscore the urgent need to understand the etiology of AD in order to develop therapeutic interventions. A popular debate among scientists has traditionally pitted those in support of Beta amyloid protein as a causative factor ("Baptists") against others who implicate tau hyperphosphorylation ("Tauists"). Considering the significance of Beta amyloid protein and hyperphosphorlyated tau protein aggregates in AD pathology, this article delves into the nature of inflammation associated with these aggregates. Aspects of inflammation focus on microglia, resident immune cells of the CNS that are activated during AD inflammation and are known to play a significant role in pathogenesis. This article discusses the role of microglia, inflammation, and the immune response as a middle ground in the debate between the "Tauists" and the "Baptists" respective positions. It explores recent advances in immunotherapy and supports continued research in and use of immunosuppressive regimens as potential therapeutic interventions for AD.

Glabe CG. · Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697, USA. · J Biol Chem. · Pubmed #18723507 No free full text.

Abstract: Amyloid oligomers are believed to play important causal roles in many types of amyloid-related degenerative diseases. Many different laboratories have reported amyloid oligomers that differ in size, morphology, toxicity, and method of preparation or purification, raising the question of the structural relationships among these oligomer preparations. The structural plasticity that has been reported to occur in amyloids formed from the same protein sequence indicates that it is quite possible that different oligomer preparations may represent distinct structural variants. In view of the difficulty in determining the precise structure of amyloids, conformation- and epitope-specific antibodies may provide a facile means of classifying amyloid oligomer structures. Conformation-dependent antibodies that recognize generic epitopes that are specifically associated with distinct aggregation states of many different amyloid-forming sequences indicate that there are at least two fundamentally distinct types of amyloid oligomers: fibrillar and prefibrillar oligomers. Classification of amyloid oligomers according to their underlying structures may be a more useful and rational approach than relying on differences in size and morphology.

Zarow C, Sitzer TE, Chui HC. · University of Southern California, Rancho Los Amigos National Rehabilitation Center, 7601 E. Imperial Highway, Medical Science Building, Room 26, Downey, CA 90242, USA. · Curr Neurol Neurosci Rep. · Pubmed #18713571 No free full text.

Abstract: Hippocampal sclerosis (HS) is a pathologic term used to describe severe loss of neurons and reactive gliosis without cystic cavitation in the CA1 sector of the hippocampus. In late life, HS is associated with hippocampal atrophy, severe amnesia, and slowly progressive dementia without clinical seizure activity. HS is difficult to distinguish clinically from Alzheimer's disease and is often diagnosed postmortem. In autopsy series, HS may be found without significant other pathology (2%-4% of cases), but it occurs frequently in combination with other vascular and neurodegenerative disorders (12%-20% of cases). HS is found bilaterally in 50% of cases and unilaterally in 50% of cases, with similar predilection for the right versus left hemisphere. The pathogenesis of HS is unknown and may be multifactorial in origin, possibly due to anoxic/ischemic injury or TDP-43-related neurodegeneration. Little is known about the prevention and treatment of late-life HS, although circumstantial evidence suggests the importance of identifying and treating vascular risk factors.

Hagerman RJ, Hall DA, Coffey S, Leehey M, Bourgeois J, Gould J, Zhang L, Seritan A, Berry-Kravis E, Olichney J, Miller JW, Fong AL, Carpenter R, Bodine C, Gane LW, Rainin E, Hagerman H, Hagerman PJ. · MIND Institute, University of California, Davis, School of Medicine, Sacramento, CA 95817, USA. · Clin Interv Aging. · Pubmed #18686748 links to  free full text

Abstract: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurological disorder that affects older adult carriers, predominantly males, of premutation alleles (55 to 200 CGG repeats) of the fragile X (FMR1) gene. Principal features of FXTAS are intention tremor, ataxia, parkinsonism, cognitive decline, and peripheral neuropathy; ancillary features include, autonomic dysfunction, and psychiatric symptoms of anxiety, depression, and disinhibition. Although controlled trials have not been carried out in individuals with FXTAS, there is a significant amount of anecdotal information regarding various treatment modalities. Moreover, there exists a great deal of evidence regarding the efficacy of various medications for treatment of other disorders (eg, Alzheimer disease) that have substantial phenotypic overlap with FXTAS. The current review summarizes what is currently known regarding the symptomatic treatment, or potential for treatment, of FXTAS.

Head E. · Department of Neurology, Institute for Brain Aging & Dementia, University of California, 1259 Gillespie Neuroscience Research Facility, Irvine, CA 92697-4540, USA. · Neurochem Res. · Pubmed #18683046 No free full text.

Abstract: Oxidative damage in the brain may lead to cognitive impairments in aged humans. Further, in age-associated neurodegenerative disease, oxidative damage may be exacerbated and associated with additional neuropathology. Epidemiological studies in humans show both positive and negative effects of the use of antioxidant supplements on healthy cognitive aging and on the risk of developing Alzheimer disease (AD). This contrasts with consistent behavioral improvements in aged rodent models. In a higher mammalian model system that naturally accumulates human-type pathology and cognitive decline (aged dogs), an antioxidant enriched diet leads to rapid learning improvements, memory improvements after prolonged treatment and cognitive maintenance. Cognitive benefits can be further enhanced by the addition of behavioral enrichment. In the brains of aged treated dogs, oxidative damage is reduced and there is some evidence of reduced AD-like neuropathology. In combination, antioxidants may be beneficial for promoting healthy brain aging and reducing the risk of neurodegenerative disease.

Henderson VW. · Departmentsof Health Research and Policy (Epidemiology), Stanford University, Stanford, California 94305-5405, USA. · Clin Obstet Gynecol. · Pubmed #18677155 No free full text.

Abstract: The natural menopause is not associated with substantial cognitive change. Limited clinical trial evidence suggests that estrogen-containing hormone therapy has little effect on cognition during midlife, but prompt initiation after surgical menopause may improve aspects of memory. Among older postmenopausal women, strong clinical trial evidence demonstrates that hormone initiation does not improve cognition. More limited clinical trial evidence indicates no improvement in Alzheimer symptoms, and the Women's Health Initiative Memory Study found an increase in dementia risk among older women. Observational findings of reduced Alzheimer risk may reflect early hormone use in younger women, or findings may be biased. Cognitive effects of selective estrogen receptor modulators are not yet well studied.

Green KN, LaFerla FM. · Department of Neurobiology and Behavior and Institute for Brain Aging and Dementia, University of California, Irvine, Irvine, CA 92697-4545, USA. · Neuron. · Pubmed #18667147 No free full text.

Abstract: Recent developments point to a critical role for calcium dysregulation in the pathogenesis of Alzheimer's disease. A novel calcium-conducting channel called CALHM1 is genetically linked to the disorder and modulates Abeta production. Calcium homeostasis has also been shown to be perturbed in dendritic spines adjacent to amyloid plaques. Finally, new studies have elucidated the role by which presenilins modulate calcium signaling, including effects on SERCA2b and gating of the IP(3) receptor, and lead to Abeta production.

Bortolato M, Chen K, Shih JC. · Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA. · Adv Drug Deliv Rev. · Pubmed #18652859 No free full text.

Abstract: Monoamine oxidases (MAOs) A and B are mitochondrial bound isoenzymes which catalyze the oxidative deamination of dietary amines and monoamine neurotransmitters, such as serotonin, norepinephrine, dopamine, beta-phenylethylamine and other trace amines. The rapid degradation of these molecules ensures the proper functioning of synaptic neurotransmission and is critically important for the regulation of emotional behaviors and other brain functions. The byproducts of MAO-mediated reactions include several chemical species with neurotoxic potential, such as hydrogen peroxide, ammonia and aldehydes. As a consequence, it is widely speculated that prolonged excessive activity of these enzymes may be conducive to mitochondrial damages and neurodegenerative disturbances. In keeping with these premises, the development of MAO inhibitors has led to important breakthroughs in the therapy of several neuropsychiatric disorders, ranging from mood disorders to Parkinson's disease. Furthermore, the characterization of MAO knockout (KO) mice has revealed that the inactivation of this enzyme produces a number of functional and behavioral alterations, some of which may be harnessed for therapeutic aims. In this article, we discuss the intriguing hypothesis that the attenuation of the oxidative stress induced by the inactivation of either MAO isoform may contribute to both antidepressant and antiparkinsonian actions of MAO inhibitors. This possibility further highlights MAO inactivation as a rich source of novel avenues in the treatment of mental disorders.

Brinton RD. · Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, School of Pharmacy Pharmaceutical Sciences Center, Los Angeles, California 90033, USA. · Adv Drug Deliv Rev. · Pubmed #18647624 No free full text.

Abstract: Estrogen-induced signaling pathways in hippocampal and cortical neurons converge upon the mitochondria to enhance mitochondrial function and to sustain aerobic glycolysis and citric acid cycle-driven oxidative phosphorylation and ATP generation. Data derived from experimental and clinical paradigms investigating estrogen intervention in healthy systems and prior to neurodegenerative insult indicate enhanced neural defense and survival through maintenance of calcium homeostasis, enhanced glycolysis coupled to the citric acid cycle (aerobic glycolysis), sustained and enhanced mitochondrial function, protection against free radical damage, efficient cholesterol trafficking and beta amyloid clearance. The convergence of E(2) mechanisms of action onto mitochondrial is also a potential point of vulnerability when activated in a degenerating neural system and could exacerbate the degenerative processes through increased load on dysregulated calcium homeostasis. The data indicate that as the continuum of neurological health progresses from healthy to unhealthy so too do the benefits of estrogen or hormone therapy. If neurons are healthy at the time of estrogen exposure, their response to estrogen is beneficial for both neuronal survival and neurological function. In contrast, if neurological health is compromised, estrogen exposure over time exacerbates neurological demise. The healthy cell bias of estrogen action hypothesis provides a lens through which to assess the disparities in outcomes across the basic to clinical domains of scientific inquiry and on which to predict future applications of estrogen and hormone therapeutic interventions sustain neurological health and to prevent age-associated neurodegenerative diseases such as Alzheimer's. Overall, E(2) promotes the energetic capacity of brain mitochondria by maximizing aerobic glycolysis (oxidative phosphorylation coupled to pyruvate metabolism). The enhanced aerobic glycolysis in the aging brain would be predicted to prevent conversion of the brain to using alternative sources of fuel such as the ketone body pathway characteristic of Alzheimer's.

Fawzi NL, Yap EH, Okabe Y, Kohlstedt KL, Brown SP, Head-Gordon T. · UCSF/UCB Joint Graduate Group in Bioengineering, Berkeley, California 94720, USA. · Acc Chem Res. · Pubmed #18646868 No free full text.

Abstract: [Figurre: see text]. Protein aggregation can be defined as the sacrifice of stabilizing intrachain contacts of the functional state that are replaced with interchain contacts to form non-functional states. The resulting aggregate morphologies range from amorphous structures without long-range order typical of nondisease proteins involved in inclusion bodies to highly structured fibril assemblies typical of amyloid disease proteins. In this Account, we describe the development and application of computational models for the investigation of nondisease and disease protein aggregation as illustrated for the proteins L and G and the Alzheimer's Abeta systems. In each case, we validate the models against relevant experimental observables and then expand on the experimental window to better elucidate the link between molecular properties and aggregation outcomes. Our studies show that each class of protein exhibits distinct aggregation mechanisms that are dependent on protein sequence, protein concentration, and solution conditions. Nondisease proteins can have native structural elements in the denatured state ensemble or rapidly form early folding intermediates, which offers avenues of protection against aggregation even at relatively high concentrations. The possibility that early folding intermediates may be evolutionarily selected for their protective role against unwanted aggregation could be a useful strategy for reengineering sequences to slow aggregation and increase folding yield in industrial protein production. The observed oligomeric aggregates that we see for nondisease proteins L and G may represent the nuclei for larger aggregates, not just for large amorphous inclusion bodies, but potentially as the seeds of ordered fibrillar aggregates, since most nondisease proteins can form amyloid fibrils under conditions that destabilize the native state. By contrast, amyloidogenic protein sequences such as Abeta 1-40,42 and the familial Alzheimer's disease (FAD) mutants favor aggregation into ordered fibrils once the free-energy barrier for forming a critical nucleus is crossed. However, the structural characteristics and oligomer size of the soluble nucleation species have yet to be determined experimentally for any disease peptide sequence, and the molecular mechanism of polymerization that eventually delineates a mature fibril is unknown. This is in part due to the limited experimental access to very low peptide concentrations that are required to characterize these early aggregation events, providing an opportunity for theoretical studies to bridge the gap between the monomer and fibril end points and to develop testable hypotheses. Our model shows that Abeta 1-40 requires as few as 6-10 monomer chains (depending on sequence) to begin manifesting the cross-beta order that is a signature of formation of amyloid filaments or fibrils assessed in dye-binding kinetic assays. The richness of the oligomeric structures and viable filament and fibril polymorphs that we observe may offer structural clues to disease virulence variations that are seen for the WT and hereditary mutants.

Schneider LS. · Department of Psychiatry, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. · Alzheimers Dement. · Pubmed #18631988 No free full text.

Abstract: In the absence of effective drugs for Alzheimer's disease (AD) and a validated roadmap or guideline for drug development, it is important to consider some of the limitations currently hampering AD drug development and some general principles for moving forward. This paper will address current barriers to developing drugs for AD, and offer new considerations for accelerating drug discovery, development, and clinical trials.

Schenk D. · Elan Pharmaceuticals, South San Francisco, CA, USA. · Alzheimers Dement. · Pubmed #18631987 No free full text.

Abstract: The need to develop meaningful therapeutics for Alzheimer's disease is beginning to reach the general awareness of the public. Matching this awareness is the accelerated pace of compounds entering clinical trials. In addition, the development of diagnostic tools, biomarkers, and imaging modalities of the past decade in AD have improved dramatically. Unfortunately, the use of these diagnostic and scientific tools in clinical trial practice has not yet aligned or optimized. Most agents still target clinical end points associated with mild to moderate AD rather than focus on modulation of the underlying pathologies. Although there are obvious practical reasons for this, meaningful progress in other areas of medicine such as cardiology and oncology have generally targeted and monitored improvement or abatement of pathology as the primary end point as a successful disease-modifying strategy. Perhaps it is time to consider a similar approach in treatment of Alzheimer's disease.