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Amyloid beta 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 precursor protein (APP), which is cleaved by beta secretase and gamma secretase to yield Aβ in a cholesterol dependent process and substrate presentation. Aβ molecules can aggregate to form flexible soluble oligomers which may exist in several forms. It is now believed that certain misfolded oligomers 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 is some evidence that misfolded Aβ can induce tau to misfold.
Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of synapse formation, neural plasticity, antimicrobial activity, and iron export. It is coded for by the gene APP and regulated by substrate presentation. APP is best known as the precursor molecule whose proteolysis generates amyloid beta (Aβ), a polypeptide containing 37 to 49 amino acid residues, whose amyloid fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients.
Secretases are enzymes that "snip" pieces off a longer protein that is embedded in the cell membrane.
Neurodegeneration is the progressive loss of structure or function of neurons, which may ultimately involve cell death. Many neurodegenerative diseases—such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, and prion diseases—occur as a result of neurodegenerative processes. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic. Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable. Biomedical research has revealed many similarities between these diseases at the sub-cellular level, including atypical protein assemblies and induced cell death. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well.
Beta-secretase 1, also known as beta-site amyloid precursor protein cleaving enzyme 1, beta-site APP cleaving enzyme 1 (BACE1), membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, and ASP2, is an enzyme that in humans is encoded by the BACE1 gene. Expression of BACE1 is observed mainly in neurons.
Gamma secretase is a multi-subunit protease complex, itself an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases. The most well-known substrate of gamma secretase is amyloid precursor protein, a large integral membrane protein that, when cleaved by both gamma and beta secretase, produces a short 37-43 amino acid peptide called amyloid beta whose abnormally folded fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients. Gamma secretase is also critical in the related processing of several other type I integral membrane proteins, such as Notch, ErbB4, E-cadherin, N-cadherin, ephrin-B2, or CD44.
Presenilins are a family of related multi-pass transmembrane proteins which constitute the catalytic subunits of the gamma-secretase intramembrane protease protein complex. They were first identified in screens for mutations causing early onset forms of familial Alzheimer's disease by Peter St George-Hyslop at the Centre for Research in Neurodegenerative Diseases at the University of Toronto, and now also at the University of Cambridge. Vertebrates have two presenilin genes, called PSEN1 that codes for presenilin 1 (PS-1) and PSEN2 that codes for presenilin 2 (PS-2). Both genes show conservation between species, with little difference between rat and human presenilins. The nematode worm C. elegans has two genes that resemble the presenilins and appear to be functionally similar, sel-12 and hop-1.
John Anthony Hardy FRS is a human geneticist and molecular biologist at the Reta Lila Weston Institute of Neurological Studies at University College London with research interests in neurological diseases.
The Roskamp Institute, was co-founded by Robert and Diane Roskamp, and Fiona Crawford and Michael Mullan in Sarasota, Florida in 2003. It is a nonprofit biomedical research facility specializing neurological research including Alzheimer's disease, traumatic brain injury, Gulf War syndrome, and posttraumatic stress disorder. It also operates an onsite neurology clinic. The Institute is focused on finding the causes and treatments for neuropsychiatric and neurodegenerative diseases.
Alpha secretases are a family of proteolytic enzymes that cleave amyloid precursor protein (APP) in its transmembrane region. Specifically, alpha secretases cleave within the fragment that gives rise to the Alzheimer's disease-associated peptide amyloid beta when APP is instead processed by beta secretase and gamma secretase. The alpha-secretase pathway is the predominant APP processing pathway. Thus, alpha-secretase cleavage precludes amyloid beta formation and is considered to be part of the non-amyloidogenic pathway in APP processing. Alpha secretases are members of the ADAM family, which are expressed on the surfaces of cells and anchored in the cell membrane. Several such proteins, notably ADAM10, have been identified as possessing alpha-secretase activity. Upon cleavage by alpha secretases, APP releases its extracellular domain - a fragment known as APPsα - into the extracellular environment in a process known as ectodomain shedding.
Cathepsin B belongs to a family of lysosomal cysteine proteases and plays an important role in intracellular proteolysis. In humans, cathepsin B is encoded by the CTSB gene. Cathepsin B is upregulated in certain cancers, in pre-malignant lesions, and in various other pathological conditions.
Michael Mullan is an English-American researcher in Alzheimer's disease and related neurodegenerative disorders. Mullan was a co-discoverer of genetic causes of Alzheimer's disease. Subsequently, he was a co-inventor on the original patents that covered three mutations in the amyloid precursor protein (APP) gene, a gene which is linked to familial Alzheimer's disease. He also co-authored articles in Nature and Nature Genetics, describing these three genetic errors; he was the senior author on two of those articles. Dr. Mullan co-discovered a specific genetic mutation, which became known as "the Swedish Mutation," because it was originally identified in DNA samples from two Swedish families whose members often developed early-onset Alzheimer's disease. These human genetic mutations were integrated into mouse DNA to create strains of mice that are being used worldwide to develop new drug treatments for Alzheimer's disease.
Presenilin-1 (PS-1) is a presenilin protein that in humans is encoded by the PSEN1 gene. Presenilin-1 is one of the four core proteins in the gamma secretase complex, which is considered to play an important role in generation of amyloid beta (Aβ) from amyloid precursor protein (APP). Accumulation of amyloid beta is associated with the onset of Alzheimer's disease.
Presenilin-2 is a protein that is encoded by the PSEN2 gene.
Amyloid-like protein 1, also known as APLP1, is a protein that in humans is encoded by the APLP1 gene. APLP1 along with APLP2 are important modulators of glucose and insulin homeostasis.
Early-onset Alzheimer's disease, also called early-onset Alzheimer's, younger-onset Alzheimer's or early-onset AD, is Alzheimer's disease diagnosed before the age of 65. It is an uncommon form of Alzheimer's, accounting for only 5–10% of all Alzheimer's cases. About 60% have a positive family history of Alzheimer’s and 13% of them are inherited in an autosomal dominant manner. Most cases of early-onset Alzheimer's, however, share the same traits as the "late-onset" form and are not caused by known genetic mutations. Little is understood about how it starts.
The Alzheimer's disease biomarkers are neurochemical indicators used to assess the risk or presence of the disease. The biomarkers can be used to diagnose Alzheimer's disease (AD) in a very early stage, but they also provide objective and reliable measures of disease progress. It is imperative to diagnose AD disease as soon as possible, because neuropathologic changes of AD precede the symptoms by years. It is well known that amyloid beta (Aβ) is a good indicator of AD disease, which has facilitated doctors to accurately pre-diagnose cases of AD. When Aβ peptide is released by proteolytic cleavage of amyloid-beta precursor protein, some Aβ peptides that are solubilized are detected in CSF and blood plasma which makes AB peptides a promising candidate for biological markers. It has been shown that the amyloid beta biomarker shows 80% or above sensitivity and specificity, in distinguishing AD from dementia. It is believed that amyloid beta as a biomarker will provide a future for diagnosis of AD and eventually treatment of AD.
Rudolph Tanzi is the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard University, and Vice-Chair of Neurology, Director of the Genetics and Aging Research Unit, and Co-Director of the Henry and Allison McCance Center for Brain Health at Massachusetts General Hospital (MGH). Dr. Tanzi has been investigating the genetics of neurological disease since a student in the 1980s when he participated in the first study that used genetic markers to find a disease gene. Dr. Tanzi co-discovered all three familial early-onset Alzheimer's disease (FAD) genes and several other neurological disease genes including that responsible for Wilson’s disease. As the leader of the Cure Alzheimer's Fund Alzheimer’s Genome Project, Dr. Tanzi has carried out multiple genome wide association studies of thousands of Alzheimer’s families leading to the identification of novel AD candidate genes, including CD33 and the first two rare mutations causing late-onset AD in the ADAM10 gene. His research on the role of zinc and copper in AD has led to clinical trials at Prana Biotechnology. He is also working on gamma secretase modulators for the prevention and treatment of Alzheimer's. He also serves as Chair of the Cure Alzheimer's Fund Research Leadership Group and Director the Cure Alzheimer’s Fund Alzheimer’s Genome Project™.
Colin Louis MastersMD is an Australian neuropathologist who researches Alzheimer's disease and other neurodegenerative disorders. He is laureate professor of pathology at the University of Melbourne.
Experimental models of Alzheimer's disease are cellular or animal models of Alzheimer's disease.
References
- ↑ Mullan M, Crawford F, Axelman K, Houlden H, Lilius L, Winblad B, Lannfelt L (August 1992). "A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid". Nature Genetics. 1 (5): 345–7. doi:10.1038/ng0892-345. PMID 1302033. S2CID 20046036.
- ↑ Wilson CA, Doms RW, Lee VM (August 1999). "Intracellular APP processing and A beta production in Alzheimer disease". Journal of Neuropathology and Experimental Neurology. 58 (8): 787–94. doi: 10.1097/00005072-199908000-00001 . PMID 10446803.
- 1 2 "Tg2576". Archived from the original on 2017-01-01. Retrieved 2016-12-31.
- ↑ Haass C, Lemere CA, Capell A, Citron M, Seubert P, Schenk D, Lannfelt L, Selkoe DJ (December 1995). "The Swedish mutation causes early-onset Alzheimer's disease by beta-secretase cleavage within the secretory pathway". Nature Medicine. 1 (12): 1291–6. doi:10.1038/nm1295-1291. PMID 7489411. S2CID 21827324.
- ↑ Webster SJ, Bachstetter AD, Nelson PT, Schmitt FA, Van Eldik LJ (2014). "Using mice to model Alzheimer's dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models". Frontiers in Genetics. 5: 88. doi: 10.3389/fgene.2014.00088 . PMC 4005958 . PMID 24795750.