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42-465: Amyloid beta ( Aβ , Abeta or beta-amyloid ) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease . The peptides derive from the amyloid-beta precursor protein (APP), which is cleaved by beta secretase and gamma secretase to yield Aβ in a cholesterol-dependent process and substrate presentation . Both neurons and oligodendrocytes produce and release Aβ in

84-451: A thioflavin ), can selectively bind to amyloid beta in vitro and in vivo. This technique, combined with PET imaging, is used to image areas of plaque deposits in those with Alzheimer's. Amyloid beta can be measured semiquantitatively with immunostaining , which also allows one to determine location. Amyloid beta may be primarily vascular, as in cerebral amyloid angiopathy , or in amyloid plaques in white matter . One sensitive method

126-466: A transcription factor , and anti-microbial activity (potentially associated with Aβ's pro- inflammatory activity). The glymphatic system clears metabolic waste from the mammalian brain, and in particular amyloid beta. A number of proteases have been implicated by both genetic and biochemical studies as being responsible for the recognition and degradation of amyloid beta; these include insulin degrading enzyme and presequence protease. The rate of removal

168-399: A diverse set of chemical manipulations on the developing product. These peptides are often cyclic and can have highly complex cyclic structures, although linear nonribosomal peptides are also common. Since the system is closely related to the machinery for building fatty acids and polyketides , hybrid compounds are often found. The presence of oxazoles or thiazoles often indicates that

210-514: A multiplicity of discrete conformational clusters by statistical analysis. By NMR-guided simulations, amyloid beta 1-40 and amyloid beta 1-42 also seem to feature highly different conformational states, with the C-terminus of amyloid beta 1-42 being more structured than that of the 1-40 fragment. Low-temperature and low-salt conditions allowed to isolate pentameric disc-shaped oligomers devoid of beta structure. In contrast, soluble oligomers prepared in

252-504: A number of isoforms of 30–51 amino acid residues in length. The most common isoforms are Aβ 40 and Aβ 42 ; the longer form is typically produced by cleavage that occurs in the endoplasmic reticulum , while the shorter form is produced by cleavage in the trans- Golgi network. Autosomal-dominant mutations in APP cause hereditary early-onset Alzheimer's disease (familial AD, fAD). This form of AD accounts for no more than 10% of all cases, and

294-409: A tangle of Aβ oligomers and regularly ordered aggregates called amyloid fibrils , a protein fold shared by other peptides such as the prions associated with protein misfolding disease, also known as proteinopathy . Research suggests that soluble oligomeric forms of the amyloid beta may be causative agents in the development of Alzheimer's disease . It is generally believed that Aβ oligomers are

336-632: A unique tertiary fold but rather populates a set of structures. As such, it cannot be crystallized and most structural knowledge on amyloid beta comes from NMR and molecular dynamics . Early NMR-derived models of a 26-aminoacid polypeptide from amyloid beta (Aβ 10–35) show a collapsed coil structure devoid of significant secondary structure content. However, the most recent (2012) NMR structure of (Aβ 1-40) has significant secondary and tertiary structure. Replica exchange molecular dynamics studies suggested that amyloid beta can indeed populate multiple discrete structural states; more recent studies identified

378-502: Is ELISA which is an immunosorbent assay which utilizes a pair of antibodies that recognize amyloid beta. Atomic force microscopy , which can visualize nanoscale molecular surfaces, can be used to determine the aggregation state of amyloid beta in vitro. Vibrational microspectroscopy is a label-free method that measures the vibration of molecules in tissue samples. Amyloid proteins like Aβ can be detected with this technique because of their high content of β-sheet structures. Recently,

420-521: Is formed after sequential cleavage of the amyloid precursor protein (APP), a transmembrane glycoprotein of undetermined function. APP can be cleaved by the proteolytic enzymes α- , β- and γ-secretase ; Aβ protein is generated by successive action of the β and γ secretases. The γ secretase, which produces the C-terminal end of the Aβ peptide, cleaves within the transmembrane region of APP and can generate

462-644: Is a chemical process that converts individual molecules into a chain consisting of a finite number of molecules. Prevention of oligomerization of Aβ has been exemplified by active or passive Aβ immunization. In this process antibodies to Aβ are used to decrease cerebral plaque levels. This is accomplished by promoting microglial clearance and/or redistributing the peptide from the brain to systemic circulation. Antibodies that target Aβ and were tested in clinical trials included aducanumab , bapineuzumab , crenezumab , gantenerumab , lecanemab , and solanezumab . Imaging compounds, notably Pittsburgh compound B , (6-OH-BTA-1,

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504-428: Is achieved by a long-range negative feedback signal released from the developed axon and taken up by the other neurite. However, no long range signaling molecule has been discovered. Alternatively, it has been suggested that the buildup of axonal growth factors in the neurite destined to become the axon means there is a depletion of axonal growth factors by default, as they must compete for the same proteins. This causes

546-410: Is complete. The development of a neurite ( neuritogenesis ) requires a complex interplay of both extracellular and intracellular signals. At every given point along a developing neurite, there are receptors detecting both positive and negative growth cues from every direction in the surrounding space. The developing neurite sums together all of these growth signals in order to determine which direction

588-480: Is estimated that at least 10% of the pharmaceutical market is based on peptide products. The peptide families in this section are ribosomal peptides, usually with hormonal activity. All of these peptides are synthesized by cells as longer "propeptides" or "proproteins" and truncated prior to exiting the cell. They are released into the bloodstream where they perform their signaling functions. Several terms related to peptides have no strict length definitions, and there

630-491: Is often overlap in their usage: Peptides and proteins are often described by the number of amino acids in their chain, e.g. a protein with 158 amino acids may be described as a "158 amino-acid-long protein". Peptides of specific shorter lengths are named using IUPAC numerical multiplier prefixes: The same words are also used to describe a group of residues in a larger polypeptide ( e.g. , RGD motif ). (See Template:Leucine metabolism in humans – this diagram does not include

672-410: Is predominantly the shorter Aβ40. Several sequences of Aβ were found in both lesions. Increases in either total Aβ levels or the relative concentration of both Aβ40 and Aβ42 (where the former is more concentrated in cerebrovascular plaques and the latter in neuritic plaques) have been implicated in the pathogenesis of both familial and sporadic Alzheimer's disease. Due to its more hydrophobic nature,

714-1582: Is released during formation of each amide bond. All peptides except cyclic peptides have an N-terminal (amine group) and C-terminal (carboxyl group) residue at the end of the peptide (as shown for the tetrapeptide in the image). There are numerous types of peptides that have been classified according to their sources and functions. According to the Handbook of Biologically Active Peptides , some groups of peptides include plant peptides, bacterial/ antibiotic peptides , fungal peptides, invertebrate peptides, amphibian/skin peptides, venom peptides, cancer/anticancer peptides, vaccine peptides, immune/inflammatory peptides, brain peptides, endocrine peptides , ingestive peptides, gastrointestinal peptides, cardiovascular peptides, renal peptides, respiratory peptides, opioid peptides , neurotrophic peptides, and blood–brain peptides. Some ribosomal peptides are subject to proteolysis . These function, typically in higher organisms, as hormones and signaling molecules. Some microbes produce peptides as antibiotics , such as microcins and bacteriocins . Peptides frequently have post-translational modifications such as phosphorylation , hydroxylation , sulfonation , palmitoylation , glycosylation, and disulfide formation. In general, peptides are linear, although lariat structures have been observed. More exotic manipulations do occur, such as racemization of L-amino acids to D-amino acids in platypus venom . Nonribosomal peptides are assembled by enzymes , not

756-451: Is significantly increased during sleep. However, the significance of the glymphatic system in Aβ clearance in Alzheimer's disease is unknown. Aβ is the main component of amyloid plaques , extracellular deposits found in the brains of people with Alzheimer's disease. Aβ can also form the deposits that line cerebral blood vessels in cerebral amyloid angiopathy . The plaques are composed of

798-553: Is some evidence that misfolded Aβ can induce tau to misfold. A study has suggested that APP and its amyloid potential is of ancient origins, dating as far back as early deuterostomes . The normal function of Aβ is not yet known. Though some animal studies have shown that the absence of Aβ does not lead to any obvious loss of physiological function, several potential activities have been discovered for Aβ, including activation of kinase enzymes , protection against oxidative stress , regulation of cholesterol transport, functioning as

840-513: Is unresolved how Aβ accumulates in the central nervous system and subsequently initiates the disease of cells. Significant efforts have been focused on the mechanisms responsible for Aβ production, including the proteolytic enzymes gamma- and β-secretases which generate Aβ from its precursor protein, APP (amyloid precursor protein). Aβ circulates in plasma, cerebrospinal fluid (CSF) and brain interstitial fluid (ISF) mainly as soluble Aβ40. Amyloid plaques contain both Aβ40 and Aβ42, while vascular amyloid

882-477: The APP V717I mutation has revealed extensive Aβ pathology throughout neuroaxis as well as widespread cerebral amyloid angiopathy (CAA). The gene for the amyloid precursor protein is located on chromosome 21 , and accordingly people with Down syndrome have a very high incidence of Alzheimer's disease. Amyloid beta is commonly thought to be intrinsically unstructured , meaning that in solution it does not acquire

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924-449: The Aβ42 is the most amyloidogenic form of the peptide. However the central sequence KLVFFAE is known to form amyloid on its own, and probably forms the core of the fibril. One study further correlated Aβ42 levels in the brain not only with onset of Alzheimer's disease, but also reduced cerebrospinal fluid pressure, suggesting that a build-up or inability to clear Aβ42 fragments may play a role into

966-705: The Neurolucida system. Weak endogenous electric fields may be used to both facilitate and direct the growth of projections from cell soma neurites, EFs of moderate strength have been used to direct and enhance neurite outgrowth in both murine , or mouse, and xenopus models. Co-culture of neurons with electrically aligned glial tissue also directs neurite outgrowth, as it is rich in neurotrophins that promote nerve growth . An undifferentiated mammalian neuron placed in culture will retract any neurites that it has already grown. 0.5 to 1.5 days after being plated in culture, several minor neurites will begin to protrude out from

1008-513: The Rac-1 pathway, the Ras-mediated pathway, the cAMP -liver kinase B1 pathway, and the calcium/calmodulin-dependent protein kinase pathway. A deficiency in any of these pathways would lead to the inability to develop a neuron. After forming one axon, the neuron must prevent all other neurites from becoming axons as well. This is known as global inhibition. It has been suggested that global inhibition

1050-459: The actin filaments are stabilized by myosin. This prevents the development of multiple axons. The neural cell adhesion molecule N-CAM simultaneously combines with another N-CAM and a fibroblast growth factor receptor to stimulate the tyrosine kinase activity of that receptor to induce the growth of neurites. There are several software kits available to facilitate neurite tracing in images such as NeuronJ (an ImageJ plugin), Neuromantic, and

1092-524: The brain, contributing to formation of amyloid plaques. Aβ molecules can aggregate to form flexible soluble oligomers which may exist in several forms. It is now believed that certain misfolded oligomers (known as "seeds") can induce other Aβ molecules to also take the misfolded oligomeric form, leading to a chain reaction akin to a prion infection. The oligomers are toxic to nerve cells . The other protein implicated in Alzheimer's disease, tau protein , also forms such prion-like misfolded oligomers, and there

1134-506: The broad chemical classes of biological polymers and oligomers , alongside nucleic acids , oligosaccharides , polysaccharides , and others. Proteins consist of one or more polypeptides arranged in a biologically functional way, often bound to ligands such as coenzymes and cofactors , to another protein or other macromolecule such as DNA or RNA , or to complex macromolecular assemblies . Amino acids that have been incorporated into peptides are termed residues . A water molecule

1176-497: The cell body simultaneously with one or more other neurites. It has been proposed that a minor neurite could extend outward until it touches an already developed axon of another neuron. At this point, the neurite will begin to differentiate into an axon. This is known as the "touch and go" model. However, this model does not explain how the first axon developed. Whatever extracellular signals may be involved in inducing axon formation are transduced through at least 4 different pathways:

1218-517: The cell body. Sometime between day 1.5 and day 3, one of the minor neurites begins to outgrow the other neurites significantly. This neurite will eventually become the axon . On days 4 to 7, the remaining minor neurites will begin differentiating into dendrites. By day 7, the neuron should be completely polarized, with a functional dendrites and an axon. A neurite growing in vivo is surrounded by thousands of extracellular signals which in turn can be modulated by hundreds of intracellular pathways, and

1260-430: The compound was synthesized in this fashion. Peptones are derived from animal milk or meat digested by proteolysis . In addition to containing small peptides, the resulting material includes fats, metals, salts, vitamins, and many other biological compounds. Peptones are used in nutrient media for growing bacteria and fungi. Peptide fragments refer to fragments of proteins that are used to identify or quantify

1302-509: The formation of Aβ fibrils was resolved in different plaque -types in Alzheimer's disease , indicating that plaques transit different stages in their development. Dual polarisation interferometry is an optical technique which can measure early stages of aggregation by measuring the molecular size and densities as the fibrils elongate. These aggregate processes can also be studied on lipid bilayer constructs. Peptide Peptides fall under

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1344-415: The mechanisms for how these competing chemical signals effect the ultimate differentiation of neurites in vivo is not precisely understood. It is known that 60% of the time the first neurite that protrudes from the cell body will become the axon. 30% of the time, a neurite not destined to become the axon protrudes from the cell body first. 10% of the time, the neurite that will become the axon protrudes from

1386-411: The most toxic. Several genetic, cell biology, biochemical and animal studies using experimental models support the concept that Aβ plays a central role in the development of Alzheimer's disease pathology. Brain Aβ is elevated in people with sporadic Alzheimer's disease. Aβ is the main constituent of brain parenchymal and vascular amyloid; it contributes to cerebrovascular lesions and is neurotoxic. It

1428-893: The nature of its possible effects, results are largely inconclusive. Aβ levels have been assessed in relation to a number of cancers, including esophageal , colorectal , lung , and hepatic , in response to observed reductions in risk for developing Alzheimer's disease in survivors of these cancers. All cancers were shown to be associated positively with increased Aβ levels, particularly hepatic cancers. This direction of association however has not yet been established. Studies focusing on human breast cancer cell lines have further demonstrated that these cancerous cells display an increased level of expression of amyloid precursor protein. Adults with Down syndrome had accumulation of amyloid in association with evidence of Alzheimer's disease, including declines in cognitive functioning, memory, fine motor movements, executive functioning, and visuospatial skills. Aβ

1470-489: The neurite will ultimately grow towards. While not all of the growth signals are known, several have been identified and characterized. Among the known extracellular growth signals are netrin , a midline chemoattractant, and semaphorin , ephrin and collapsin , all inhibitors of neurite growth. Young neurites are often packed with microtubule bundles, the growth of which is stimulated by neurotrophic factors , such as nerve growth factor (NGF). Tau proteins can aid in

1512-420: The pathology. The " amyloid hypothesis " — that the plaques are responsible for the pathology of Alzheimer's disease — is accepted by the majority of researchers, but is not conclusively established. An alternative hypothesis is that amyloid oligomers rather than plaques are responsible for the disease. While Aβ has been implicated in cancer development, prompting studies on a variety of cancers to elucidate

1554-427: The pathway for β-leucine synthesis via leucine 2,3-aminomutase) Neurite A neurite or neuronal process refers to any projection from the cell body of a neuron . This projection can be either an axon or a dendrite . The term is frequently used when speaking of immature or developing neurons, especially of cells in culture , because it can be difficult to tell axons from dendrites before differentiation

1596-461: The presence of detergents seem to feature substantial beta sheet content with mixed parallel and antiparallel character, different from fibrils; computational studies suggest an antiparallel beta-turn-beta motif instead for membrane-embedded oligomers. Immunotherapy may stimulate the host immune system to recognize and attack Aβ, or provide antibodies that either prevent plaque deposition or enhance clearance of plaques or Aβ oligomers. Oligomerization

1638-434: The ribosome. A common non-ribosomal peptide is glutathione , a component of the antioxidant defenses of most aerobic organisms. Other nonribosomal peptides are most common in unicellular organisms , plants , and fungi and are synthesized by modular enzyme complexes called nonribosomal peptide synthetases . These complexes are often laid out in a similar fashion, and they can contain many different modules to perform

1680-562: The source protein. Often these are the products of enzymatic degradation performed in the laboratory on a controlled sample, but can also be forensic or paleontological samples that have been degraded by natural effects. Peptides can perform interactions with proteins and other macromolecules. They are responsible for numerous important functions in human cells, such as cell signaling, and act as immune modulators. Indeed, studies have reported that 15-40% of all protein-protein interactions in human cells are mediated by peptides. Additionally, it

1722-404: The stabilization of microtubules by binding to the microtubules, protecting them from microtubule severing proteins. Even after the microtubules have stabilized, the cytoskeleton of the neuron remains dynamic. Actin filaments retain their dynamic properties in the neurite that will become the axon in order to push the microtubules bundles outward to extend the axon. In all other neurites however,

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1764-462: The vast majority of AD is not accompanied by such mutations. However, familial Alzheimer's disease is likely to result from altered proteolytic processing. This is evidenced by the fact that many mutations that lead to fAD occur near γ-secretase cleavage sites on APP. One of the most common mutations causing fAD, London Mutation , occurs at codon 717 of the APP gene, and results in a valine to isoleucine amino acid substitution. Histochemical analysis of

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