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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-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 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 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.
Amyloid plaques are extracellular deposits of amyloid beta (Aβ) protein that present 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 aging, but large numbers of plaques and neurofibrillary tangles are characteristic features of Alzheimer's disease. 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. Plaques form when Aβ misfolds and aggregates into oligomers and longer polymers, the latter of which are characteristic of amyloid.
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.
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, is a class of diseases in which certain proteins become structurally abnormal, and thereby disrupt the function of cells, tissues and organs of the body.
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-beta precursor protein (APP). Accumulation of amyloid beta is associated with the onset of Alzheimer's disease.
Early-onset Alzheimer's disease (EOAD), also called younger-onset Alzheimer's disease (YOAD), 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.
Peter Henry St George-Hyslop is a British and Canadian medical scientist, neurologist and molecular geneticist who is known for his research into neurodegenerative diseases. St George-Hyslop is one of the most cited authors in the field of Alzheimer's disease research. He has identified a number of key genes that are responsible for nerve cell degeneration and early-onset forms of Alzheimer's disease. These include the discovery of the presenilins, Nicastrin, TREM2, Apolipoprotein E and SORL1 genes. Presenilin mutations are the most common cause of familial Alzheimer's disease. St George-Hyslop also co-led the discovery of the gene for the amyloid precursor protein.
Rudolph Emile 'Rudy' Tanzi a professor of Neurology at Harvard University, 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).
p3 peptide also known as amyloid β- peptide (Aβ)17–40/42 is the peptide resulting from the α- and γ-secretase cleavage from the amyloid precursor protein (APP). It is known to be the major constituent of diffuse plaques observed in Alzheimer's disease (AD) brains and pre-amyloid plaques in people affected by Down syndrome. However, p3 peptide's role in these diseases is not truly known yet.
The ion channel hypothesis of Alzheimer's disease (AD), also known as the channel hypothesis or the amyloid beta ion channel hypothesis, is a more recent variant of the amyloid hypothesis of AD, which identifies amyloid beta (Aβ) as the underlying cause of neurotoxicity seen in AD. While the traditional formulation of the amyloid hypothesis pinpoints insoluble, fibrillar aggregates of Aβ as the basis of disruption of calcium ion homeostasis and subsequent apoptosis in AD, the ion channel hypothesis in 1993 introduced the possibility of an ion-channel-forming oligomer of soluble, non-fibrillar Aβ as the cytotoxic species allowing unregulated calcium influx into neurons in AD.
Virginia Man-Yee Lee is a Chinese-born American biochemist and neuroscientist who specializes in the research of Alzheimer's disease. She is the current John H. Ware 3rd Endowed Professor in Alzheimer's Research at the Department of Pathology and Laboratory Medicine, and the director of the Center for Neurodegenerative Disease Research and co-director of the Marian S. Ware Alzheimer Drug Discovery Program at the Perelman School of Medicine, University of Pennsylvania. She received the 2020 Breakthrough Prize in Life Sciences.
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 controversial 2006 Nature paper, "A specific amyloid-β protein assembly in the brain impairs memory". Lesné's work in the 2006 publication and others has been investigated since June 2022 on charges that he manipulated images to inflate the role of Aβ*56 in Alzheimer's. Retracted in 2024, the paper was foundational in the hypothesis that one specific toxic oligomer of the amyloid beta protein, known as Aβ*56, caused memory impairment in Alzheimer's, aligned with the prevailing amyloid hypothesis.
David Lozoff Brody is an American neurologist, academic, and author most known for his research on the clinical treatment of traumatic brain injury (TBI) and neurodegenerative diseases in civilian and military personnel. He is a Clinical Neurologist at the Walter Reed National Military Medical Center and a professor of Neurology at Uniformed Services University of the Health Sciences, as well as a professor of Neurology and Biomedical Engineering at Washington University.
References
- ↑ "Dr. Dennis J. Selkoe Neurologist in Boston, MA". U.S. News & World Report . Retrieved 2020-12-03.
- ↑ "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. Archived from the original on October 1, 2020. Retrieved 2020-12-07.
{{cite web}}: CS1 maint: unfit URL (link) - ↑ "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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