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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 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.
Amyloid plaques are extracellular deposits of the amyloid beta (Aβ) protein mainly in the grey matter of the brain. Degenerative neuronal elements and an abundance of microglia and astrocytes can be associated with amyloid plaques. Some plaques occur in the brain as a result of senescence (aging), but large numbers of plaques and neurofibrillary tangles are characteristic features of Alzheimer's disease. Abnormal neurites in amyloid plaques are tortuous, often swollen axons and dendrites. The neurites contain a variety of organelles and cellular debris, and many of them include characteristic paired helical filaments, the ultrastructural component of neurofibrillary tangles. The plaques are highly variable in shape and size; in tissue sections immunostained for Aβ, they comprise a log-normal size distribution curve with an average plaque area of 400-450 square micrometers (µm²). The smallest plaques, which often consist of diffuse deposits of Aβ, are particularly numerous. The apparent size of plaques is influenced by the type of stain used to detect them, and by the plane through which they are sectioned for analysis under the microscope. Plaques form when Aβ misfolds and aggregates into oligomers and longer polymers, the latter of which are characteristic of amyloid. Misfolded and aggregated Aβ is thought to be neurotoxic, especially in its oligomeric state.
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, and prion diseases. 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; however research has shown that the two major contributing factors to neurodegeneration are oxidative stress and inflammation. Biomedical research has revealed many similarities between these diseases at the subcellular 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.
Karen K. Hsiao Ashe is a professor at the Department of Neurology and Neuroscience at the University of Minnesota (UMN) Medical School, where she holds the Edmund Wallace and Anne Marie Tulloch Chairs in Neurology and Neuroscience. She is the founding director of the N. Bud Grossman Center for Memory Research and Care, and her specific research interest is memory loss resulting from Alzheimer's disease and related dementias. Her research has included the development of an animal model of Alzheimer's.
The biochemistry of Alzheimer's disease, the most common cause of dementia, is not yet very well understood. Alzheimer's disease (AD) has been identified as a proteopathy: a protein misfolding disease due to the accumulation of abnormally folded amyloid beta (Aβ) protein in the brain. Amyloid beta is a short peptide that is an abnormal proteolytic byproduct of the transmembrane protein amyloid-beta precursor protein (APP), whose function is unclear but thought to be involved in neuronal development. The presenilins are components of proteolytic complex involved in APP processing and degradation.
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. 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.
Nicastrin, also known as NCSTN, is a protein that in humans is encoded by the NCSTN gene.
In medicine, proteinopathy, or proteopathy, protein conformational disorder, or protein misfolding disease refers to a class of diseases in which certain proteins become structurally abnormal, and thereby disrupt the function of cells, tissues and organs of the body. Often the proteins fail to fold into their normal configuration; in this misfolded state, the proteins can become toxic in some way or they can lose their normal function. The proteinopathies include such diseases as Creutzfeldt–Jakob disease and other prion diseases, Alzheimer's disease, Parkinson's disease, amyloidosis, multiple system atrophy, and a wide range of other disorders. The term proteopathy was first proposed in 2000 by Lary Walker and Harry LeVine.
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.
Early-onset Alzheimer's disease, also called younger-onset Alzheimer's, 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 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 Emile 'Rudy' 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™.
YoungSoo Kim is a South Korean chemist. Kim is an associate professor in Department of Pharmacy at Yonsei University.
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.
Hilal Lashuel is an American-Yemeni neuroscientist and chemist, currently an associate professor at the EPFL. His research focuses on protein misfolding and aggregation in the pathogenesis of Alzheimer's and Parkinson's diseases.
Sylvain E. Lesné is a French neuroscientist and associate professor at the Department of Neuroscience at the University of Minnesota (UMN) Medical School, known for his research into Alzheimer's disease. He is the primary author of a 2006 Nature paper that is foundational in the hypothesis that one specific toxic oligomer of the amyloid beta protein, known as Aβ*56, is a cause of memory impairment in Alzheimer's, aligned with the prevailing amyloid hypothesis.
References
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- ↑ "DENNIS SELKOE, M.D." Cure Alzheimer's Fund . Curealz. 2010-05-30. Retrieved 2020-12-03.
- ↑ "Institute of Medicine News: IOM elects 64 new members, five foreign associates". American Association for the Advancement of Science . Christine Stencel. 2005-10-24. Retrieved 2020-12-07.
- ↑ "Biography – The Laboratory of Dennis J. Selkoe, MD". Brigham and Women's Hospital . Selkoe Laboratory. Retrieved 2020-12-03.
- ↑ "ADDING MULTIMEDIA MetLife Foundation Marks 20th Anniversary of Awards for Medical Research in Alzheimer's Disease; Two Decades of Investing in Science and Scientists". Business Wire . 2006-02-14. Retrieved 2020-12-07.
- ↑ "The Laboratory of Dennis J. Selkoe, MD". Brigham and Women's Hospital . Selkoe Laboratory. Retrieved 2020-12-03.
- ↑ "The Laboratory of Dennis J. Selkoe, MD". Selkoe Lab. Retrieved 2020-12-07.
- ↑ "Dennis Selkoe, MD". World Neuroscience Innovation Forum. 2017-03-27. Retrieved 2020-12-07.
- ↑ "Biography". Selkoe Lab. Retrieved 2020-12-07.
- ↑ "Dennis J. Selkoe, M.D." Prothena Corporation plc. Retrieved 26 August 2021.
- ↑ "D. Selkoe". Semantic Scholar . Retrieved 14 November 2022.
- ↑ "AAIC 2019 - Awards". Alzheimer's Association . AAIC. 2019. Retrieved 2020-12-03.
- ↑ "DENNIS J. SELKOE (1943), USA". Royal Netherlands Academy of Arts and Sciences . KNAW. Archived from the original on 2020-09-28.
- ↑ "Rochester neuroscientist receives $1 million Alzheimer's research award". American Association for the Advancement of Science . Tom Rickey. 1999-11-16. Retrieved 2020-12-03.
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