Alzheimer Disease: Massachusetts

Drachman DA. · Department of Neurology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA. · Curr Neurol Neurosci Rep. · Pubmed #17618530 No free full text.

This publication has no abstract.

Kim D, Tsai LH. · Howard Hughes Medical Institute, MIT Picower Institute for Learning and Memory, Cambridge, MA 02139, USA. · Cell. · Pubmed #19524503 No free full text.

Abstract: The APP-processing pathway is a pathological component of Alzheimer's disease (AD), but there is no consensus regarding the physiological functions of APP and its products. Two studies (Nikolaev et al., 2009; Lauren et al., 2009) link the physiological and pathological aspects of APP processing. They show that the APP products, N-APP and Abeta42, are ligands for death receptor 6 and cellular prion protein, respectively, which are important in nervous system development and synaptic suppression.

Wright JF, Doherty ME, Dumas LG. · Norwell Visiting Nurse Association and Hospice, 91 Longwater Circle, Norwell, MA 02061, USA. · Nurs Clin North Am. · Pubmed #19463677 No free full text.

Abstract: Just as the voices of people with Alzheimer's disease are driving changes, the voices of caregivers can also facilitate change, which is vital now and for the future. Caregivers play an important role in the educational process.

Tan ZS, Vasan RS. · Division of Aging, Brigham and Women's Hospital, Boston, MA 02160, USA. · J Alzheimers Dis. · Pubmed #19276542 No free full text.

Abstract: Thyroid dysfunction has been implicated as a cause of reversible cognitive impairment and as such, the thyroid stimulating hormone has long been part of the screening laboratory test for dementia. Recently, several population-based studies demonstrated an association between hypo- or hyperthyroidism and Alzheimer's disease. This review discusses the role of thyroid hormone in the normal development and regulation of central nervous system functions and summarizes the studies that have linked thyroid function and dementia risk. Finally, it explores possible biological mechanisms to explain this association, including the direct effects of thyroid hormone on cerebral amyloid processing, neurodegeneration and thyrotropin-mediated mechanisms and vascular mediated enhancement of Alzheimer's disease risk.

Desilets AR, Gickas JJ, Dunican KC. · Massachusetts College of Pharmacy and Health Sciences-Worcester/Manchester, MA, USA. · Ann Pharmacother. · Pubmed #19240260 No free full text.

Abstract: OBJECTIVE: To review the role of huperzine A in the treatment of Alzheimer's disease (AD). DATA SOURCES: A literature search was conducted through MEDLINE (1950-September week 2, 2008), EMBASE (all years), Google Scholar, International Pharmaceutical Abstracts, and a bibliographic review of relevant articles. Key words included huperzine, huperin, Huperzia serrata, and Alzheimer's disease. STUDY SELECTION AND DATA EXTRACTION: All clinical trials published in the English language that evaluated huperzine A in patients with AD were included in this review. Articles published in Chinese were included when English abstracts or electronic translation technology were available. DATA SYNTHESIS: AD is a progressive neurodegenerative brain disorder for which there is no cure; available therapies only decrease cognitive decline. Huperzine A, an alkaloid derived from Chinese club moss (H. serrata), acts as a selective inhibitor of acetylcholinesterase and may also display neuroprotective properties. Preliminary data suggest that huperzine A may improve cognition; studies ranging from 8 to 12 weeks have found improvements in the Mini-Mental State Examination score of 1-5 points. CONCLUSIONS: Although use of huperzine A has shown promising results in patients with AD, data supporting its use are limited by weak study design. Largescale, randomized, placebo-controlled trials are necessary to establish the role of huperzine A in the treatment of AD.

Viswanathan A, Rocca WA, Tzourio C. · Department of Neurology and Clinical Trials Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. · Neurology. · Pubmed #19171835 No free full text.

Abstract: In recent years, accumulating evidence has suggested that vascular risk factors contribute to Alzheimer disease (AD). Vascular dementia had been traditionally considered secondary to stroke and vascular disease. It has been traditionally distinguished from AD, considered to be a purely neurodegenerative form of dementia. However, in light of this more recent literature, it appears that there is a spectrum: ranging from patients with pure vascular dementia to patients with pure AD and including a large majority of patients with contributions from both Alzheimer and vascular pathologies. In this article, we discuss the impact of vascular risk factors on AD and its consequences at the individual level and at the population level by highlighting the concept of attributable risk. We then discuss the key questions and next steps involved in designing a therapeutic trial to control vascular risk factors for the prevention of dementia.

Wolfe MS. · Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, 77 Avenue Louis Pasteur, Boston, MA 02115 USA. · Semin Cell Dev Biol. · Pubmed #19162210 No free full text.

Abstract: gamma-Secretase is a membrane-embedded proteolytic complex composed of presenilin and three other subunits. The gamma-secretase complex generates the amyloid beta-peptide of Alzheimer's disease but also plays important roles in normal physiology, especially in signaling from the Notch receptor. How this hydrolytic enzyme works in a hydrophobic environment is largely unanswered, but mutagenesis and chemical probes have offered insight. gamma-Secretase is an important therapeutic target, although mechanism-based toxicity presents a serious obstacle. Agents that lower amyloid beta-peptide production while leaving important normal functions of gamma-secretase intact are promising therapeutic leads. Inhibition of Notch signaling by gamma-secretase inhibitors, which is undesirable for the prevention or treatment of Alzheimer's disease, may be beneficial for the treatment of a variety of cancers.

Wolfe MS. · Center for Neurologic Diseases, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. · BMC Neurosci. · Pubmed #19090992 links to  free full text

Abstract: The amyloid-beta peptide (Abeta), implicated in the pathogenesis of Alzheimer's disease (AD), is produced through sequential proteolysis of the Abeta precursor protein (APP) by beta- and gamma-secretases. Thus, blocking either of these two proteases, directly or indirectly, is potentially worthwhile toward developing AD therapeutics. beta-Secretase is a membrane-tethered pepsin-like aspartyl protease suitable for structure-based design, whereas gamma-secretase is an unusual, heterotetrameric membrane-embedded aspartyl protease. While gamma-secretase inhibitors entered clinical trials first due to their superior pharmacological properties (for example, brain penetration) over beta-secretase inhibitors, it has since become clear that gamma-secretase inhibitors can cause mechanism-based toxicities owing to interference with the proteolysis of another gamma-secretase substrate, the Notch receptor. Strategies for targeting Abeta production at the gamma-secretase level without blocking Notch signalling will be discussed. Other strategies utilizing cell-based screening have led to the identification of novel Abeta lowering agents that likewise leave Notch proteolysis intact. The mechanism by which these agents lower Abeta is unknown, but these compounds may ultimately reveal new targets for AD therapeutics.

Zhou J, Yu Q, Zou T. · Department of Medicine, Program in Neuroscience, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA. · BMC Neurosci. · Pubmed #19090983 links to  free full text

Abstract: Tau aggregation is one of the major features in Alzheimer's disease and in several other tauopathies, including frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), and progressive supranuclear palsy (PSP). More than 35 mutations in the tau gene have been identified from FTDP-17 patients. A group of these mutations alters splicing of exon 10, resulting in an increase in exon 10 inclusion into tau mRNA. Abnormal splicing with inclusion of exon 10 into tau mRNA has also been observed in PSP and AD patients. These results indicate that abnormal splicing of exon 10, leading to the production of tau with exon 10, is probably one of the mechanisms by which tau accumulates and aggregates in tauopathic brains. Therefore, modulation of exon 10 splicing in the tau gene could potentially be targeted to prevent tauopathies. To identify small molecules or compounds that could potentially be developed into drugs to treat tauopathies, we established a cell-based high-throughput screening assay. In this review, we will discuss how realistic, specific biological molecules can be found to regulate exon 10 splicing in the tau gene for potential treatment of tauopathies.

Rogers JT, Bush AI, Cho HH, Smith DH, Thomson AM, Friedlich AL, Lahiri DK, Leedman PJ, Huang X, Cahill CM. · Department of Psychiatry, Neurochemistry Laboratory, Massachusetts General Hospital, Charlestown, MA 02129, USA. · Biochem Soc Trans. · Pubmed #19021541 No free full text.

Abstract: The essential metals iron, zinc and copper deposit near the Abeta (amyloid beta-peptide) plaques in the brain cortex of AD (Alzheimer's disease) patients. Plaque-associated iron and zinc are in neurotoxic excess at 1 mM concentrations. APP (amyloid precursor protein) is a single transmembrane metalloprotein cleaved to generate the 40-42-amino-acid Abetas, which exhibit metal-catalysed neurotoxicity. In health, ubiquitous APP is cleaved in a non-amyloidogenic pathway within its Abeta domain to release the neuroprotective APP ectodomain, APP(s). To adapt and counteract metal-catalysed oxidative stress, as during reperfusion from stroke, iron and cytokines induce the translation of both APP and ferritin (an iron storage protein) by similar mechanisms. We reported that APP was regulated at the translational level by active IL (interleukin)-1 (IL-1-responsive acute box) and IRE (iron-responsive element) RNA stem-loops in the 5' untranslated region of APP mRNA. The APP IRE is homologous with the canonical IRE RNA stem-loop that binds the iron regulatory proteins (IRP1 and IRP2) to control intracellular iron homoeostasis by modulating ferritin mRNA translation and transferrin receptor mRNA stability. The APP IRE interacts with IRP1 (cytoplasmic cis-aconitase), whereas the canonical H-ferritin IRE RNA stem-loop binds to IRP2 in neural cell lines, and in human brain cortex tissue and in human blood lysates. The same constellation of RNA-binding proteins [IRP1/IRP2/poly(C) binding protein] control ferritin and APP translation with implications for the biology of metals in AD.

Yankner BA, Lu T. · Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA. · J Biol Chem. · Pubmed #18957434 No free full text.

This publication has no abstract.

Wolfe MS. · Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. · J Biol Chem. · Pubmed #18948254 No free full text.

Abstract: Tau deposition is found in a variety of neurodegenerative brain diseases. The identification of tau mutations that cause familial dementia demonstrated that aberrant Tau alone could cause neurodegenerative disease and suggested that Tau likely plays a role in other cases in which Tau deposits are found, most notably Alzheimer disease. The mechanisms by which tau mutations cause neurodegeneration vary and are unclear to some degree, but evidence supports changes in alternative splicing, phosphorylation state, interaction with tubulin, and self-association into filaments as important contributing factors.

El Khoury J, Luster AD. · Division of Rheumatology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. · Trends Pharmacol Sci. · Pubmed #18835047 No free full text.

Abstract: In Alzheimer's disease (AD), and other conditions affecting integrity of the blood-brain barrier, microglia can originate in the bone marrow, migrate into the blood and enter the brain in a chemokine-dependent manner. CCR2, a chemokine receptor that controls mononuclear phagocyte infiltration into the brain in multiple sclerosis, bacterial meningitis and neuropathic pain, also regulates microglia accumulation in mouse models of AD. CCR2 deficiency leads to lower microglia accumulation and higher brain beta-amyloid (Abeta) levels, indicating that early microglial accumulation promotes Abeta clearance. In support of this protective role, enhancing microglia accumulation delays progression of AD. AD mice that constitutively express interleukin-1 in the brain, or that are deficient in peripheral mononuclear phagocyte transforming growth factor-beta signaling, have increased microglia accumulation around beta-amyloid plaques and reduced AD-like pathology. Regulating microglia recruitment into the brain is a novel therapeutic strategy to delay or stop progression of AD. Here, we review the role of microglia in AD and the mechanisms of their accumulation and discuss implications for AD therapy.

Bertram L, Tanzi RE. · Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Department of Neurology, Massachusetts General Hospital, 114 16th Street, Charlestown, Massachusetts 02129, USA. · Nat Rev Neurosci. · Pubmed #18802446 No free full text.

Abstract: The genetic underpinnings of Alzheimer's disease (AD) remain largely elusive despite early successes in identifying three genes that cause early-onset familial AD (those that encode amyloid precursor protein (APP) and the presenilins (PSEN1 and PSEN2)), and one genetic risk factor for late-onset AD (the gene that encodes apolipoprotein E (APOE)). A large number of studies that aimed to help uncover the remaining disease-related loci have been published in recent decades, collectively proposing or refuting the involvement of over 500 different gene candidates. Systematic meta-analyses of these studies currently highlight more than 20 loci that have modest but significant effects on AD risk. This Review discusses the putative pathogenetic roles and common biochemical pathways of some of the most genetically and biologically compelling of these potential AD risk factors.

Cohen JT, Neumann PJ. · Center for the Evaluation of Value and Risk in Health, Institute for Clinical Research and Health Policy Studies, Tufts-New England Medical Center, Boston, MA, USA. · Alzheimers Dement. · Pubmed #18631970 No free full text.

Abstract: Decision analytic policy models for Alzheimer's disease (AD) enable researchers and policy makers to investigate questions about the costs and benefits of a wide range of existing and potential screening, testing, and treatment strategies. Such models permit analysts to compare existing alternatives, explore hypothetical scenarios, and test the strength of underlying assumptions in an explicit, quantitative, and systematic way. Decision analytic models can best be viewed as complementing clinical trials both by filling knowledge gaps not readily addressed by empirical research and by extrapolating beyond the surrogate markers recorded in a trial. We identified and critiqued 13 distinct AD decision analytic policy models published since 1997. Although existing models provide useful insights, they also have a variety of limitations. (1) They generally characterize disease progression in terms of cognitive function and do not account for other distinguishing features, such as behavioral symptoms, functional performance, and the emotional well-being of AD patients and caregivers. (2) Many describe disease progression in terms of a limited number of discrete states, thus constraining the level of detail that can be used to characterize both changes in patient status and the relationships between disease progression and other factors, such as residential status, that influence outcomes of interest. (3) They have focused almost exclusively on evaluating drug treatments, thus neglecting other disease management strategies and combinations of pharmacologic and nonpharmacologic interventions. Future AD models should facilitate more realistic and compelling evaluations of various interventions to address the disease. An improved model will allow decision makers to better characterize the disease, to better assess the costs and benefits of a wide range of potential interventions, and to better evaluate the incremental costs and benefits of specific interventions used in conjunction with other disease management strategies.

Bush AI, Tanzi RE. · The Mental Health Research Institute, Parkville, Victoria, Australia. · Neurotherapeutics. · Pubmed #18625454 links to  free full text

Abstract: Alzheimer's disease is the most common form of dementia in the elderly, and it is characterized by elevated brain iron levels and accumulation of copper and zinc in cerebral beta-amyloid deposits (e.g., senile plaques). Both ionic zinc and copper are able to accelerate the aggregation of Abeta, the principle component of beta-amyloid deposits. Copper (and iron) can also promote the neurotoxic redox activity of Abeta and induce oxidative cross-linking of the peptide into stable oligomers. Recent reports have documented the release of Abeta together with ionic zinc and copper in cortical glutamatergic synapses after excitation. This, in turn, leads to the formation of Abeta oligomers, which, in turn, modulates long-term potentiation by controlling synaptic levels of the NMDA receptor. The excessive accumulation of Abeta oligomers in the synaptic cleft would then be predicted to adversely affect synaptic neurotransmission. Based on these findings, we have proposed the "Metal Hypothesis of Alzheimer's Disease," which stipulates that the neuropathogenic effects of Abeta in Alzheimer's disease are promoted by (and possibly even dependent on) Abeta-metal interactions. Increasingly sophisticated pharmaceutical approaches are now being implemented to attenuate abnormal Abeta-metal interactions without causing systemic disturbance of essential metals. Small molecules targeting Abeta-metal interactions (e.g., PBT2) are currently advancing through clinical trials and show increasing promise as disease-modifying agents for Alzheimer's disease based on the "metal hypothesis."

Wolfe MS. · Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. · Neurotherapeutics. · Pubmed #18625450 links to  free full text

Abstract: The 4-kDa amyloid beta-peptide (Abeta) is strongly implicated the pathogenesis of Alzheimer's disease (AD), and this peptide is cut out of the amyloid beta-protein precursor (APP) by the sequential action of beta- and gamma-secretases. gamma-Secretase is a membrane-embedded protease complex that cleaves the transmembrane region of APP to produce Abeta, and this protease is a top target for developing AD therapeutics. A number of inhibitors of the gamma-secretase complex have been identified, including peptidomimetics that block the active site, helical peptides that interact with the initial substrate docking site, and other less peptide-like, more drug-like compounds. To date, one gamma-secretase inhibitor has advanced into late-phase clinical trials for the treatment of AD, but serious concerns remain. The gamma-secretase complex cleaves a number of other substrates, and gamma-secretase inhibitors cause in vivo toxicities by blocking proteolysis of one essential substrate, the Notch receptor. Thus, compounds that modulate gamma-secretase, rather than inhibit it, to selectively alter Abeta production without hindering signal transduction from the Notch receptor would be more ideal. Such modulators have been discovered and advanced, with one compound in late-phase clinical trials, renewing interest in gamma-secretase as a therapeutic target.

Staropoli JF. · Department of Pathology, Massachusetts General Hospital, Gray-Jackson 249, MGH, 55 Fruit St Boston, MA 02114-2696, USA. · Bioessays. · Pubmed #18623069 No free full text.

Abstract: Dysregulation of genes that control cell-cycle progression and DNA repair is a hallmark of tumorigenesis. It is becoming increasingly apparent, however, that these defects also contribute to degeneration of post-mitotic neurons under certain conditions. The gene for ataxia-telangiectasia mutated (ATM) is a prototype for this dual mechanism of action, with loss-of-function mutations causing not only selective degeneration of cerebellar neurons but also increased susceptibility to breast cancer and hematologic malignancy. Increased dosage of amyloid precursor protein in Down syndrome (trisomy 21) predisposes to dementia of Alzheimer type and may also contribute to acute leukemia and transient myeloproliferative disorder. The gene parkin, loss-of-function mutations in which account for about half of cases of early-onset Parkinson disease, has been identified as a candidate tumor suppressor gene by several groups. Parkin is deleted or downregulated in several tumor types, and its re-expression sensitizes derivative cell lines to inhibitors of cell-cycle progression. The overlap of molecular pathways implicated in cancer and neurodegeneration challenges long-held notions about differentiated cellular states and may open the door to novel therapeutic approaches to both groups of disorders.

Calabrese EJ. · Environmental Health Sciences Division, School of Public Health, University of Massachusetts, Amherst, Massachusetts 01003, USA. · Crit Rev Toxicol. · Pubmed #18568864 No free full text.

Abstract: This article provides an evaluation of the dose-response features of drugs that are intended to improve memory, some of which have been used in the treatment of Alzheimer's disease (AD). A common feature of these drugs is that they act via an inverted U-shaped dose response, consistent with the hormetic dose response model. This article assesses historical foundations that lead to the development of AD drugs, their dose-response features and how the quantitative features of such dose responses affected drug discovery and development, and the successes and possible failures of such agents in preclinical and clinical settings. This story begins about 150 years ago with the discovery of an active agent in the Calabar bean plant called physostigmine, its unfolding medical applications, and its implications for dose-response relationships, memory enhancement, and improved drug discovery activities. The article also demonstrates the occurrence of U-shaped dose responses for memory with numerous endogenous agonists including neurosteroids, various peptides (e.g., vasopressin, CCK-8, neuropeptide Y), and other agents (e.g., epinephrine, antagonists for platelet activity factor and nicotinic receptors), supporting the generalizability of the hormetic biphasic dose response. Finally, the significance of the U-shaped dose response is critical for successful clinical application, since it defines the therapeutic window.

Zhang M. · Department of Biology, Synta Pharmaceuticals, 125 Hartwell Avenue, Lexington, MA 02421, USA. · Front Biosci. · Pubmed #18508646 No free full text.

Abstract: Extensive research has been carried out to elucidate the mechanism of neurodegenerative diseases, with special emphasis on lysosomal storage disease (LSD) and Alzheimer's disease (AD). Studies have outlined complicated profiles in both types of disorders for the role of endocytosis in disease pathogenesis and progression. Recent discoveries relating endocytosis to the pathological origin and therapeutic strategy of the diseases have yet to be addressed. In this review, I attempt to demonstrate a comprehensive analysis on the endocytic mechanism of the disease. I propose that LSD could be classified as a late endosomal trafficking disorder. I also highlight that the most critical cellular event in AD--the producing, processing, and trafficking of Abeta42 peptide--dynamically involves the entire endocytic system. I further analyze pipeline drug targets, summarize the development status of current new drugs, share thoughts on potential therapeutic strategies, and reveal that many such strategies are in close association with endocytosis. I emphasize that thoroughly understanding pathologically-relevant endocytic events is the key factor in speeding up discovery and development of novel drugs.

Solomon PR, Murphy CA. · Department of Psychology, Program in Neuroscience, Williams College, Williamstown, MA, USA. · Expert Rev Neurother. · Pubmed #18457534 No free full text.

Abstract: Recently, focus on early detection, diagnosis and treatment of Alzheimer's disease (AD) has been increasing. The rationale is that, as with any other serious illness, early intervention will lead to better outcomes for patients and families. Despite the intuitive appeal of this rationale, there is discussion and even debate regarding the issues surrounding early detection and treatment. This review begins with a futuristic case that is aimed at focusing this discussion/debate and then proceeds to consider each of the issues including: should AD screening be part of routine physical examinations? is the amyloid hypothesis correct?: implications for diagnosis and treatment? can neuroimaging studies be used to detect brain amyloid? can symptomatic medications be combined to facilitate cognition? can cognitive rehabilitation programs facilitate cognition? and can immunotherapy and other plaque-busting therapies modify the progression of AD?

Hernán MA, Alonso A, Logroscino G. · Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA. · Epidemiology. · Pubmed #18414087 No free full text.

Abstract: We conducted a systematic review of published prospective studies that estimated the association between smoking and the incidence of Alzheimer disease and dementia. The relative rate for smokers versus nonsmokers ranged from 0.27 to 2.72 for Alzheimer disease (12 studies) and from 0.38 to 1.42 for dementia (6 studies). The minimum age at entry (range: 55-75 years) explained much of the between-study heterogeneity in relative rates. We conjecture that selection bias due to censoring by death may be the main explanation for the reversal of the relative rate with increasing age.

Xia W. · Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Curr Alzheimer Res. · Pubmed #18393802 No free full text.

Abstract: Mutations in two genes, presenilin 1 (PS1) and its homologue presenilin 2 (PS2), account for a majority of early onset familial Alzheimer disease cases which are characterized by intracellular neurofibrillary tangles and extracellular amyloid fibrils composed of the amyloid beta protein (Abeta). Abeta is derived from sequential cleavages of Amyloid Precursor Protein (APP) by beta-secretase and gamma-secretase, the latter is composed of four components, PS1, nicastrin (NCT), presenilin enhancer 2 (PEN-2), and anterior pharynx defective (APH-1). These components not only maintain the stability of the gamma-secretase complex but also regulate the activity of presenilinase, the protease responsible for the cleavage of full length PS1 into N-terminal and C-terminal fragments (NTF/CTF). We have previously shown that endoproteolysis of PS1 into NTF/CTF by presenilinase requires two critical aspartate residues, suggesting that PS1 may undergo autoproteolysis; full length PS1 complexes with NCT, PEN-2, APH-1 and forms the presenilinase. While these two aspartate residues are necessary for the endoproteolysis of full length PS1, they are equally critical for the gamma-secretase cleavage of multiple substrates, and it is hypothesized that the full length PS1/presenilinase is the zymogen of gamma-secretase. The inhibition profiles of presenilinase and gamma-secretase are illustrated by their biochemical similarity but are pharmacologically distinct. Since the uncleaved PS1 loop may obstruct the entry of gamma-secretase substrates to the docking site of the gamma-secretase complex, investigation of presenilinase inhibitors interfering with substrate-docking may facilitate a novel approach to identify APP specific gamma-secretase inhibitors.

Wolfe MS. · Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA. · Curr Alzheimer Res. · Pubmed #18393800 links to  free full text

Abstract: Gamma-secretase is a multi-protein complex that proteolyzes the transmembrane region of the amyloid beta-peptide (Abeta) precursor (APP), producing the Abeta peptide implicated in the pathogenesis of Alzheimer's disease (AD). This protease has been a top target for AD, and various inhibitors have been identified, including transition-state analogue inhibitors that interact with the active site, helical peptides that interact with the initial substrate docking site, and other less peptide-like, more drug-like compounds. Although one gamma-secretase inhibitor has advanced into late-phase clinical trials, concerns about inhibiting this protease remain. The protease complex cleaves a number of other substrates, and in vivo toxicities observed with gamma-secretase inhibitors are apparently due to blocking one particularly important substrate, the Notch receptor. Thus, the potential of gamma-secretase as therapeutic target likely depends on the ability to selectively inhibit Abeta production without hindering Notch proteolysis (i.e., modulation rather than inhibition). The discovery of gamma-secretase modulators has revived gamma-secretase as an attractive target and has so far resulted in one compound in late-phase clinical trials. The identification of other modulators in a variety of structural classes raise the hope that more promising agents will soon be in the pipeline.

Kinoshita J, Clark T. · Alzheimer Research Forum, Waltham, MA, USA. · Methods Mol Biol. · Pubmed #18368375 No free full text.

Abstract: The Alzheimer Research Forum Web site ( http://www.alzforum.org ) is an independent research project to develop an online community resource to manage scientific knowledge, information, and data about Alzheimer disease (AD). Its goals are to promote rapid communication, research efficiency, and collaborative, multidisciplinary interactions. Introducing new knowledge management approaches to AD research has a potentially large societal value. AD is among the leading causes of disability and death in older people. According to the Alzheimer's Association, four million Americans currently suffer from AD. That number is expected to escalate to over 10 million in coming decades. Patients progress from memory loss to a bedridden state over many years and require near-constant care. In addition to imposing a heavy burden on family caregivers and society at large, AD and related neurodegenerative disorders are among the most complex and challenging in biomedicine. Researchers have produced an abundance of data implicating diverse biological mechanisms. Important factors include genes, environmental risks, changes in cell functions, DNA damage, accumulation of misfolded proteins, cell death, immune responses, changes related to aging, and reduced regenerative capacity. Yet there is no agreement on the fundamental causes of AD. The situations regarding Parkinson, Huntington, and amyotrophic lateral sclerosis (ALS) are similar. The challenge of integrating so much data into testable hypotheses and unified concepts is formidable. What is more, basic understanding of these diseases needs to intersect with an equally complex universe of pharmacology, medicinal chemistry, animal studies, and clinical trials. In this chapter, we will describe the approaches developed by Alzforum to achieve knowledge integration through information technology and virtual community-building. We will also propose some future directions in the application of Web-based knowledge management systems in neuromedicine.