What makes amyloid beta

Cerebrovascular transport of Alzheimer's amyloid beta and apolipoproteins J and E: possible anti-amyloidogenic role of the blood-brain barrier. Life Sci ; 59 : — P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model. Neurovascular pathways and Alzheimer amyloid beta-peptide. Brain Pathol ; 15 : 78— Metabolic regulation of brain Abeta by neprilysin.

Science ; : —2. Clearing the brain's amyloid cobwebs. Neuron ; 32 : — The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics. Clearance of Alzheimer's Abeta peptide: the many roads to perdition. Neuron ; 43 : —8.

Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. Nat Med ; 9 : —7. Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides.

Nat Med ; 10 : — Plasma amyloid beta-peptide and incipient Alzheimer's disease. Ann Neurol ; 46 : —6. Plasma A[beta]40 and A[beta]42 and Alzheimer's disease: relation to age, mortality, and risk. Neurology ; 61 : — Apolipoprotein E, amyloid, and Alzheimer disease. Mol Interv ; 2 : —75, Presenilin redistribution associated with aberrant cholesterol transport enhances beta-amyloid production in vivo.

J Neurosci ; 23 : —9. Stroke ; 35 : — Human blood-brain barrier receptors for Alzheimer's amyloid-beta —Asymmetrical binding, endocytosis, and transcytosis at the apical side of brain microvascular endothelial cell monolayer. Receptor for advanced glycation endproducts RAGE and the complications of diabetes. Ageing Res Rev ; 1 : 1— Method for measurement of the blood-brain barrier permeability in the perfused mouse brain: application to amyloid-beta peptide in wild type and Alzheimer's Tg mice.

J Neurosci Meth ; : — PLoS One ; 11 : e Holtzman DM. J Mol Neurosci ; 17 : — Human and murine ApoE markedly alters A beta metabolism before and after plaque formation in a mouse model of Alzheimer's disease. Neurobiol Dis ; 9 : — Gene transfer of human ApoE isoforms results in differential modulation of amyloid deposition and neurotoxicity in mouse brain.

Sci Transl Med ; 5 : ra Brain amyloid-beta oligomers in ageing and Alzheimer's disease. Characterization of copper interactions with alzheimer amyloid beta peptides: identification of an attomolar-affinity copper binding site on amyloid beta Enhancement of beta-amyloid peptide A-beta -mediated neurotoxicity by glutamine-synthetase. J Neurochem ; 65 : — Alzheimer's amyloid beta-peptide associated free radicals increase rat embryonic neuronal polyamine uptake and ornithine decarboxylase activity: protective effect of vitamin E.

Neurosci Lett ; : 17— J Neurosci ; 15 : — Review: Alzheimer's amyloid beta-peptide-associated free radical oxidative stress and neurotoxicity. Ezeani M, Omabe M. A new perspective of lysosomal cation channel-dependent homeostasis in Alzheimer's disease. Mol Neurobiol ; 53 : —8. Nature ; : —6. Neuronal death induced by nanomolar Amyloid beta is mediated by primary phagocytosis of neurons by microglia. Innate immunity in Alzheimer's disease.

Nat Immunol ; 16 : — Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuronal cells. J Cell Biol ; : 41— Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer's disease brain is associated with mitochondrial dysfunction.

Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons. EMBO J ; 25 : — Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides.

Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiol Rev ; 77 : — Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nat Neurosci ; 2 : —6. Specific spatial learning deficits become severe with age in beta-amyloid precursor protein transgenic mice that harbor diffuse beta-amyloid deposits but do not form plaques. Abeta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease.

Hardy J, Allsop D. Amyloid deposition as the central event in the etiology of Alzheimer's disease. Trend Pharmacol Sci ; 12 : —8. Alzheimer-type neuropathology in transgenic mice overexpressing VF beta-amyloid precursor protein. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science ; : 99— Autosomal-dominant Alzheimer's disease mutations at the same codon of amyloid precursor protein differentially alter A beta production.

J Neurochem ; : —9. Tanzi RE, Bertram L. Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective. Bertram L, Tanzi RE.

Alzheimer's disease: one disorder, too many genes? Association of apolipoprotein epsilon 4 allele and neuropathologic findings in patients with dementia. Acta Neuropathol ; 90 : — Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease.

Reitz C. Dyslipidemia and the risk of Alzheimer's disease. Curr Atheroscler Rep ; 15 : Exercise counteracts declining hippocampal function in aging and Alzheimer's disease. Neurobiol Dis ; 57 : 47— Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med ; 1 : a Cell Dis ; 2 : Amyloid-independent mechanisms in Alzheimer's disease pathogenesis.

Robakis NK. Mechanisms of AD neurodegeneration may be independent of Abeta and its derivatives. Neurobiol Aging ; 32 : —9. Cdk5: mediator of neuronal development, death and the response to DNA damage. Mech Ageing Dev ; : — ApoE4 induces Abeta42, tau, and neuronal pathology in the hippocampus of young targeted replacement apoE4 mice.

Mol Neurodegener ; 8 : Doi: Immunocytochemical and lectin histochemical studies of plaques and tangles in Down's syndrome patients at different ages. Prog Clin Biol Res ; : — The keystone of Alzheimer pathogenesis might be sought in a beta physiology. Neuroscience ; : 26— APP intracellular domain impairs adult neurogenesis in transgenic mice by inducing neuroinflammation.

PLoS One ; 5 : e Alzheimer's disease-like pathological features in transgenic mice expressing the APP intracellular domain. Kepp KP. Ten challenges of the amyloid hypothesis of Alzheimer's disease.

J Alzheimer's Disease ; 55 : — Shen ZX. Brain cholinesterases: II. The molecular and cellular basis of Alzheimer's disease. Med Hypotheses ; 63 : — Wenk GL. Neuropathologic changes in Alzheimer's disease. J Clin Psychiatry ; 64 Suppl 9 : 7— The cholinergic hypothesis of Alzheimer's disease: a review of progress.

J Neurol Neurosurg Psychiatry ; 66 : — Genome-wide association studies in Alzheimer disease. Arch Neurol ; 65 : — Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease. N Engl J Med ; : — Meta-analysis of 74, individuals identifies 11 new susceptibility loci for Alzheimer's disease.

Nat Genet ; 45 : —8. Tau proteins and neurofibrillary degeneration. Brain Pathol ; 1 : — Deane R, Zlokovic BV. Role of the blood-brain barrier in the pathogenesis of Alzheimer's disease. Curr Alzheimer Res ; 4 : —7. Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia.

J Neuroinflamm ; 6 : 1. Amyloid beta-protein oligomers and Alzheimer's disease. Alzheimers Res Ther ; 5 : Differential effects of oligomeric and fibrillar amyloid-beta on astrocyte-mediated inflammation. Neurobiol Dis ; 18 : — Inhibition of Alzheimer's beta-amyloid induced vasoactivity and proinflammatory response in microglia by a cGMP-dependent mechanism. Exp Neurol ; : — Implication of the small GTPase Rac1 in the generation of reactive oxygen species in response to beta-amyloid in C6 astroglioma cells.

Biochem J ; : — The Alzheimer's disease-associated Amyloid beta-protein is an antimicrobial peptide. PLoS One ; 5. Amyloid-beta peptide protects against microbial infection in mouse and worm models of Alzheimer's disease. Sci Transl Med ; 8 : ra Med Lett Drugs Ther ; 57 : —6.

The efficacy and safety of donepezil in patients with Alzheimer's disease: Results of a US multicentre, randomized, double-blind, placebo-controlled trial.

Dementia ; 7 : — Bryson HM, Benfield P. Drug Aging ; 10 : —9. Preclinical investigation of the functional effects of memantine and memantine combined with galantamine or donepezil.

Neuropsychopharmacology ; 32 : — Adding memantine to therapy with rivastigmine in patients with mild to moderate Alzheimer's disease: Results of a week pilot study.

Neurology ; 64 : A—A Targeting the neurotoxic species in Alzheimer's disease: inhibitors of Abeta oligomerization. Inhibition and disaggregation of alpha-synuclein oligomers by natural polyphenolic compounds. FEBS Lett ; : — Antioxidant and other biological activities of phenols from olives and olive oil. Med Res Rev ; 22 : 65— Oleuropein, the bitter principle of olives, enhances nitric oxide production by mouse macrophages.

Life Sci ; 62 : —6. The olive constituent oleuropein exhibits anti-ischemic, antioxidative, and hypolipidemic effects in anesthetized rabbits. J Nutr ; : —9. Capping of abeta42 oligomers by small molecule inhibitors. Biochemistry ; 53 : — Calpain inhibition prevents amyloid-beta-induced neurodegeneration and associated behavioral dysfunction in rats. Neuropharmacology ; 59 : — Aromatic small molecules remodel toxic soluble oligomers of amyloid beta through three independent pathways.

Abstr Pap Am Chem S ; Selective destabilization of soluble amyloid beta oligomers by divalent metal ions. Biochem Biophys Res Commun ; : —5. Generic inhibition of amyloidogenic proteins by two naphthoquinone-tryptophan hybrid molecules. Proteins ; 80 : — Neurobiol Dis ; 46 : — Inhibition of amyloid-beta aggregation by coumarin analogs can be manipulated by functionalization of the aromatic center.

Bioorgan Med Chem ; 19 : — Identification of antihypertensive drugs which inhibit Amyloid-beta protein oligomerization. J Alzheimers Dis ; 16 : 49— A novel inhibitor of amyloid beta Abeta peptide aggregation: from high throughput screening to efficacy in an animal model of Alzheimer disease.

Therapeutic strategies for Alzheimer's disease in clinical trials. Pharmacol Rep ; 68 : — Towards disease-modifying treatment of Alzheimer's disease: drugs targeting beta-amyloid.

Curr Alzheimer Res ; 7 : 40— AZD a novel, orally active BACE1 inhibitor with high potency and permeability and markedly slow off-rate kinetics. J Alzheimers Dis ; 50 : — Molecule of the month. Drug News Perspect ; 21 : Adherence to antiretroviral therapy in managed care members in the United States: a retrospective claims analysis. J Manage Care Pharm ; 20 : 86— Therapeutic effect of CHF, a new gamma-secretase modulator, in a mouse model of scrapie.

Prion ; 6 : 62— J Clin Invest ; : —9. Antiamyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimer's disease. Neuron ; 51 : — Identification of a beta-secretase activity, which truncates amyloid beta-peptide after its presenilin-dependent generation. Potential therapeutic strategies for Alzheimer's disease targeting or beyond.

Beta-Amyloid: insights from clinical trials. BioMed Res Int ; : Amyloid-ss-directed immunotherapy for Alzheimer's disease. J Int Med ; : — Molecular basis for mid-region amyloid-beta capture by leading Alzheimer's disease immunotherapies.

Sci Rep ; 5 : Profile of gantenerumab and its potential in the treatment of Alzheimer's disease. Drug Des Devel Ther ; 7 : — Human plasma contains cross-reactive Abeta conformer-specific IgG antibodies.

Biochemistry ; 47 : —6. Human antibodies against amyloid beta peptide: a potential treatment for Alzheimer's disease. BI Angel, T. Cerebrospinal fluid proteome of patients with acute Lyme disease. Proteome Res. Human papillomavirus type is commonly present in skin tumors.

Ashby, E. Atwood, C. Cerebrovascular requirement for sealant, anti-coagulant and remodeling molecules that allow for the maintenance of vascular integrity and blood supply. Brain Res. Bagnato, S. Neuroreport 28, — Balin, B. Identification and localization of Chlamydia pneumoniae in the Alzheimer's brain. Chlamydophila pneumoniae and the etiology of late-onset Alzheimer's disease. Ball, M. Limbic predilection in Alzheimer dementia: is reactivated herpesvirus involved?

PubMed Abstract Google Scholar. Intracerebral propagation of Alzheimer's disease: strengthening evidence of a herpes simplex virus etiology. Alzheimers Dement. Bateman, R. A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system.

Batton, C. Alzheimers Res. Google Scholar. Bird, S. Bishop, G. The amyloid hypothesis: let sleeping dogmas lie? Aging 23, — Physiological roles of amyloid-beta and implications for its removal in Alzheimer's disease.

Drugs Aging 21, — The amyloid paradox: amyloid-beta-metal complexes can be neurotoxic and neuroprotective. Bitel, C. Black, R. A single ascending dose study of bapineuzumab in patients with Alzheimer disease.

Alzheimer Dis. Blasko, I. Experimental traumatic brain injury in rats stimulates the expression, production and activity of Alzheimer's disease beta-secretase BACE Neural Trans. Blockx, I. Boche, D. Reduction of aggregated Tau in neuronal processes but not in the cell bodies after Abeta42 immunisation in Alzheimer's disease.

Acta Neuropathol. Boelen, E. Bourgade, K. Biogerontology 16, 85— Bowles, E. Risk of Alzheimer's disease or dementia following a cancer diagnosis. Brody, D. Amyloid-beta dynamics correlate with neurological status in the injured human brain. Science , — Bueche, C.

Buhimschi, I. Protein misfolding, congophilia, oligomerization, and defective amyloid processing in preeclampsia. Busche, M. Carnevale, D. Pathophysiological links among hypertension and Alzheimer's disease. High Blood Press. Inverse and direct cancer comorbidity in people with central nervous system disorders: a meta-analysis of cancer incidence in , participants of 50 observational studies. Charidimou, A. Cerebral amyloid angiopathy with and without hemorrhage: evidence for different disease phenotypes.

Neurology 84, — Chen, X. A lack of amyloid beta plaques despite persistent accumulation of amyloid beta in axons of long-term survivors of traumatic brain injury. Chou, C. Septicemia is associated with increased risk for dementia: a population-based longitudinal study.

Oncotarget 8, — Chuang, J. Cirrito, J. Synaptic activity regulates interstitial fluid amyloid-beta levels. Neuron 48, — Clarke, J. Overexpression of APP provides neuroprotection in the absence of functional benefit following middle cerebral artery occlusion in rats. Coric, V. Targeting prodromal Alzheimer disease with avagacestat: a randomized clinical trial. JAMA Neurol.

Cullen, K. Microvascular pathology in the aging human brain: evidence that senile plaques are sites of microhaemorrhages.

Aging 27, — D'Andrea, M. Intracellular Consequences of Amyloid in Alzheimer's Disease. Amsterdam: Academic Press. Deweerdt, S. Comparative biology: naked ambition.

Nature , S60—S DiFrancesco, J. Dominguez, D. Doody, R. A phase 3 trial of semagacestat for treatment of Alzheimer's disease. Dreses-Werringloer, U. Initial characterization of Chlamydophila Chlamydia pneumoniae cultured from the late-onset Alzheimer brain.

Driver, J. Inverse association between cancer and Alzheimer's disease: results from the Framingham Heart Study. BMJ e Dubessy, A. Superficial siderosis of the central nervous system: a rare cause of dementia with therapeutic consequences. Age Ageing 41, — Dueholm, M. Evolutionary insight into the functional amyloids of the pseudomonads. Edrey, Y. Aging 34, — Eli Lilly and Company Fedele, E.

Ageing Dev. Ferguson, B. Axonal damage in acute multiple sclerosis lesions. Brain Pt 3 , — Ferrer, I. Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer's disease. Ferrero, J. First-in-human, double-blind, placebo-controlled, single-dose escalation study of aducanumab BIIB in mild-to-moderate Alzheimer's disease. Fleisher, A. Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease.

Fox, N. Neurology 64, — Frain, L. Association of cancer and Alzheimer's disease risk in a national cohort of veterans. Freedman, D. Toggle navigation PDB Educational portal of. Molecule of the Month. Amyloid-beta Precursor Protein Cell-clogging amyloids form when proteins improperly aggregate Amyloid-beta precursor protein. Flexible portions that are not included in the structures are shown with dots, and the membrane is shown schematically in gray.

Like Dr. Jekyll and Mr. Hyde, some seemingly innocent proteins have evil alter egos. The amyloid-beta precursor protein is an important example.

It is a large membrane protein that normally plays an essential role in neural growth and repair. However, later in life, a corrupted form can destroy nerve cells, leading to the loss of thought and memory in Alzheimer's disease. Amyloid-beta precursor protein APP is a complicated protein with many functions.

It is found on the surface of cells throughout the body. Like many membrane-tethered proteins, it is composed of several domains connected by flexible linkers, making it difficult to study as one intact piece. Looking to the PDB, we can find four pieces of APP, including three domains that extend on the outside of the cell from top to bottom in blue, PDB entries 1mwp , 1owt , and 1rw6 , and a special peptide that crosses the membrane in green, from PDB entry 1iyt.

Aksenov, M. Enhancement of beta-amyloid peptide A beta -mediated neurotoxicity by glutamine synthetase. Alzheimers Dement. Anandatheerthavarada, H. Cell Biol. Arslanova, D. BMC Biotechnol.

Baranello, R. Alzheimer Res. Barsoum, M. Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons. EMBO J.

Baruch, K. Ben Khalifa, N. Bhalla, A. The location and trafficking routes of the neuronal retromer and its role in amyloid precursor protein transport. Bordji, K. Activation of extrasynaptic, but not synaptic, NMDA receptors modifies amyloid precursor protein expression pattern and increases amyloid-ss production. Google Scholar. Burdick, D. Buxbaum, J. Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor.

Cai, H. BACE1 is the major beta-secretase for generation of Abeta peptides by neurons. Carey, R. Inhibition of dynamin-dependent endocytosis increases shedding of the amyloid precursor protein ectodomain and reduces generation of amyloid beta protein.

BMC Cell Biol. Carvalho, K. A new brain metalloendopeptidase which degrades the Alzheimer beta-amyloid peptide producing soluble fragments without neurotoxic effects. PubMed Abstract Google Scholar. Caster, A. Recruitment of the Mint3 adaptor is necessary for export of the amyloid precursor protein APP from the Golgi complex.

Chartier-Harlin, M. Nature , — Cirrito, J. Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron 48, — Clarke, J. Overexpression of APP provides neuroprotection in the absence of functional benefit following middle cerebral artery occlusion in rats. Crowther, D. Neuroscience , — Mitochondrial dysfunction in neurodegenerative diseases and cancer.

De Strooper, B. Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex. Neuron 38, 9— Devi, L. Do Carmo, S. Doody, R. Dugan, J. The Ras-related GTP-binding protein, Rab1B, regulates early steps in exocytic transport and processing of beta-amyloid precursor protein. Eckman, E. Elder, G. Sinai J.