Alzheimer Disease: New England

Snyder PJ, Pearn AM. · Clinical Division, Department of Psychology, University of Connecticut, Storrs, CT, USA; Child Study Center, Yale University School of Medicine, New Haven, CT, USA. · Alzheimers Dement. · Pubmed #19595928 No free full text.

Abstract: In February 1871, the great naturalist Charles Darwin received a letter from Dr. James-Crichton Browne, who was serving as Director of the largest lunatic asylum in England. Darwin had been introduced to Crichton-Browne 2 years earlier by Henry Maudsley, who believed that the young psychiatrist could provide Darwin with clinical examples of extreme emotional expression, to aid him in preparing to write Expression of the Emotions in Man and Animals (1872). This particular letter from Crichton-Browne contained the first and only reference to "premature dotage" or "senile decay" found anywhere in Darwin's entire corpus of correspondence, which amounted to more than 80,000 pages of handwritten letters to nearly 2,000 individuals throughout his lifetime. Moreover, this letter from Crichton-Browne, received by Darwin 36 years before the first case report of senile dementia by Professor Alois Alzheimer, explicitly noted that such premature dotage is the result of "brain wasting." Crichton-Browne believed that senile dementia was the result of a central nervous system disease, with the emotional lability observed in his patients linked inextricably to the disease process. This early hypothesis, of interest to Darwin in 1871, anticipated the groundbreaking neurohistopathologic research and case description by Alzheimer 36 years later, and has been confirmed by all clinical research in this field since 1907. This concordance between psychological symptoms and Alzheimer's disease continues to be an important area of study, leading to recent advances in our understanding of the genetics, neurobiology, and neurochemistry of psychiatric illness in older adults.

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.

Zawia NH, Lahiri DK, Cardozo-Pelaez F. · Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA. · Free Radic Biol Med. · Pubmed #19245828 No free full text.

Abstract: Alzheimer disease (AD) is a progressive neurodegenerative disorder whose clinical manifestations appear in old age. The sporadic nature of 90% of AD cases, the differential susceptibility to and course of the illness, as well as the late age onset of the disease suggest that epigenetic and environmental components play a role in the etiology of late-onset AD. Animal exposure studies demonstrated that AD may begin early in life and may involve an interplay between the environment, epigenetics, and oxidative stress. Early life exposure of rodents and primates to the xenobiotic metal lead (Pb) enhanced the expression of genes associated with AD, repressed the expression of others, and increased the burden of oxidative DNA damage in the aged brain. Epigenetic mechanisms that control gene expression and promote the accumulation of oxidative DNA damage are mediated through alterations in the methylation or oxidation of CpG dinucleotides. We found that environmental influences occurring during brain development inhibit DNA-methyltransferases, thus hypomethylating promoters of genes associated with AD such as the beta-amyloid precursor protein (APP). This early life imprint was sustained and triggered later in life to increase the levels of APP and amyloid-beta (Abeta). Increased Abeta levels promoted the production of reactive oxygen species, which damage DNA and accelerate neurodegenerative events. Whereas AD-associated genes were overexpressed late in life, others were repressed, suggesting that these early life perturbations result in hypomethylation as well as hypermethylation of genes. The hypermethylated genes are rendered susceptible to Abeta-enhanced oxidative DNA damage because methylcytosines restrict repair of adjacent hydroxyguanosines. Although the conditions leading to early life hypo- or hypermethylation of specific genes are not known, these changes can have an impact on gene expression and imprint susceptibility to oxidative DNA damage in the aged brain.

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.

Lafreniere D, Mann N. · Division of Otolaryngology, Department of Surgery, University of Connecticut Health Center, 263 Farmington Avenue, MC-6228, Farmington, CT 06030-6228, USA. · Otolaryngol Clin North Am. · Pubmed #19134495 No free full text.

Abstract: More than 35 million people in the United States are aged 65 years or older. Of people aged more than 80 years, 62% to 80% have a significant reduction in their sense of smell, which can adversely affect their safety and nutritional status. This article reviews the anatomy of smell and discusses the known and theorized etiologies of smell loss in the elderly population.

Salloway S, Correia S. · Department of Neurology, Butler Hospital, Providence, RI 02906, USA. · Cleve Clin J Med. · Pubmed #19122111 links to  free full text

Abstract: Basic research is bringing a much-needed infusion of optimism and urgency to the clinical diagnosis and treatment of Alzheimer disease. Some of its risk factors may be modifiable, and although current drugs offer only modest benefit, true disease-modifying drugs are on the horizon. This review is aimed at primary care physicians, who are the first clinicians to see patients with Alzheimer disease and are responsible for their ongoing care throughout the course of their dementia.

Papp KV, Walsh SJ, Snyder PJ. · Department of Psychology, University of Connecticut, Storrs, CT, USA. · Alzheimers Dement. · Pubmed #19118809 No free full text.

Abstract: BACKGROUND: Research on the potential effects of cognitive intervention in healthy elderly has been motivated by (1) the apparent effectiveness of cognitive rehabilitation in Alzheimer's disease (AD) patients; (2) the face validity of bolstering skills eventually burdened by disease; (3) interest in low-cost/noninvasive methods of preventing or delaying onset of disease; (4) the epidemiologic research suggesting protective effects of educational attainment and lifelong participation in cognitively stimulating activities; (5) the burgeoning industry of brain training products and requisite media attention; and (6) the aging world population. METHODS: We performed a systematic review with meta-analytic techniques to analyze randomized controlled trials of cognitive interventions in healthy elderly. RESULTS: The weighted mean effect size (Cohen's d) of cognitive intervention across all outcome measures after training was .16 (95% confidence interval, .138 to .186). The existing literature is limited by a lack of consensus on what constitutes the most effective type of cognitive training, insufficient follow-up times, a lack of matched active controls, and few outcome measures showing changes in daily functioning, global cognitive skills, or progression to early AD. CONCLUSIONS: Our review was limited by a small, heterogeneous, and methodologically limited literature. Within this literature, we found no evidence that structured cognitive intervention programs delay or slow progression to AD in healthy elderly. Further work that accounts for the limitations of past efforts and subsequent clear and unbiased reporting to the public of the state and progress of research on this topic will help the elderly make informed decisions about a range of potential preventive lifestyle measures including cognitive intervention.

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.

Jalbert JJ, Daiello LA, Lapane KL. · Department of Community Health - Epidemiology, Warren Alpert School of Medicine at Brown University, 121 South Main, Box G, Providence, RI 02912, USA. · Epidemiol Rev. · Pubmed #18635578 No free full text.

Abstract: Dementia of the Alzheimer type is a progressive, fatal neurodegenerative condition characterized by deterioration in cognition and memory, progressive impairment in the ability to carry out activities of daily living, and a number of neuropsychiatric symptoms. This narrative review summarizes the literature regarding descriptive epidemiology, clinical course, and characteristic neuropathological changes of dementia of the Alzheimer type. Although there are no definitive imaging or laboratory tests, except for brain biopsy, for diagnosis, brief screening instruments and neuropsychiatric test batteries used to assess the disease are discussed. Insufficient evidence exists for the use of biomarkers in clinical practice for diagnosis or disease management, but promising discoveries are summarized. Optimal treatment requires both nonpharmacological and pharmacological interventions, yet none have been shown to modify the disease's clinical course. This review describes the current available options and summarizes promising new avenues for treatment. Issues related to the care of persons with dementia of the Alzheimer type, including caregiver burden, long-term care, and the proliferation of dementia special care units, are discussed. Although advances have been made, more research is needed to address the gaps in our understanding of the disease.

Jackson CE, Snyder PJ. · Department of Psychology, University of Connecticut, Storrs, CT, USA. · Alzheimers Dement. · Pubmed #18631990 No free full text.

Abstract: BACKGROUND: Successful early detection of mild cognitive impairment (MCI) and Alzheimer's disease demands the identification of biomarkers capable of distinguishing individuals with prodromal or early cognitive impairment from healthy aging adults. Many laboratories are engaged in the discovery and validation of a wide array of potential genetic, proteomic, cognitive, and other types of biomarkers. METHODS: This review focuses on the application of quantitative electroencephalography (qEEG) and event-related potential (ERP) technologies as markers of prodromal impairment and early disease progression. It is the aim of this review to critically assess where this field currently stands, as well as future directions for EEG biomarker development. RESULTS: As a neuroimaging tool that is relatively inexpensive, potentially portable, and capable of providing high-density spatial mapping, qEEG offers a noninvasive, rapid, and replicable method for assessing age-related and disease-related neurophysiologic change. CONCLUSIONS: As different signature changes associated with particular stages of disease burden are identified and validated, we anticipate expanded application of qEEG as a reliable and sensitive biomarker(s) of MCI and early Alzheimer's disease.

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.

Salloway S, Mintzer J, Weiner MF, Cummings JL. · Department of Clinical Neuroscience, Division of Biology and Medicine, Brown Medical School, Providence, RI, USA. · Alzheimers Dement. · Pubmed #18631951 No free full text.

Abstract: Alzheimer's disease (AD) is a chronic, progressive, neurodegenerative disorder that places a substantial burden on patients, their families, and society. The disease affects approximately 5 million individuals in the United States, with an annual cost of care greater than $100 billion. During the past dozen years, several agents have been approved that enhance cognition and global function of AD patients, and recent advances in understanding AD pathogenesis has led to the development of numerous compounds that might modify the disease process. A wide array of antiamyloid and neuroprotective therapeutic approaches are under investigation on the basis of the hypothesis that amyloid beta (A beta) protein plays a pivotal role in disease onset and progression and that secondary consequences of A beta generation and deposition, including tau hyperphosphorylation and neurofibrillary tangle formation, oxidation, inflammation, and excitotoxicity, contribute to the disease process. Interventions in these processes with agents that reduce amyloid production, limit aggregation, or increase removal might block the cascade of events comprising AD pathogenesis. Reducing tau hyperphosphorylation, limiting oxidation and excitotoxicity, and controlling inflammation might be beneficial disease-modifying strategies. Potentially neuroprotective and restorative treatments such as neurotrophins, neurotrophic factor enhancers, and stem cell-related approaches are also under investigation.

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.