Amyloid Peptides

Amyloid Peptides
Definition Amyloids are filamentous protein deposits ranging in size from nanometres to microns and composed of aggregated peptide beta-sheets formed from parallel or anti-parallel alignments of peptide beta-strands.

Structural Characteristics
Using Solid-State NMR (SSNMR), in conjunction with computational energy minimization procedures, Tycko and coworkers have put forward a structure of the amyloid fibrils formed from the 40-residue form of the amyloid ß peptide (Aß1-40) at pH 7.4 and 24oC under quiescent conditions1, 2, 3. In this structure, each Aß1-40 molecule contributes a pair of ß-strands, spanning approximately residues 12–24 and 30–40, to the core region of the fibrils. These strands, connected by the loop 25–29, are not part of the same ß-sheet, however, but participate in the formation of two distinct ß-sheets within the same protofilament. The different Aß molecules2, 3 are stacked on to each other, in a parallel arrangement and in register, at least from residue 9 to 39. By invoking additional experimental constraints, such as the diameter of the protofilaments observed using Transmission electron microscopy (TEM), and the mass per unit length, measured by means of scanning transmission electron microscopy (STEM) 1, 2 it has been suggested that a single protofilament is composed of four ß-sheets separated by distances of ~10 Å.

Mode of Action
Alzheimer's disease (AD) is a result of filamentous deposits of amyloid, which define the disease at the molecular level, occur within perikarya, axons, dendrites, and terminals of neurons as neurofibrillary tangles (NFT), in the extracellular neuropil as amyloid plaques (APC), and around blood vessels as amyloid congophilic angiopathy (ACA). The amyloid deposits apparently occur in the terminal zones of neurons that develop NFT. It has been suggested that the major constituent of both APC and ACA has been shown to be a 4.5-kDa amyloid protein originally termed "beta-protein" or "amyloid A4" which we now denote as "beta A4." Amyloid beta A4 protein is proteolytically derived from a transmembrane protein termed amyloid precursor protein (APP) which is encoded by a widely expressed gene on chromosome 214.

Functions
Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers: A study was conducted to investigate the possible involvement of Ca2+ signaling disruptions in amyloid-induced cytotoxicity, homogeneous preparations of disease-related amyloids (beta, prion, islet amyloid polypeptide, polyglutamine, and lysozyme) in various aggregation states were made and tested their actions on fluo-3-loaded SH-SY5Y cells. Application of oligomeric forms of all amyloids tested (0.6-6 µg /ml) rapidly (approximately 5 s) elevated intracellular Ca2+, whereas equivalent amounts of monomers and fibrils did not. Ca2+signals evoked by Abeta42 oligomers persisted after depletion of intracellular Ca2+ stores, and small signals remained in Ca2+-free medium, indicating contributions from both extracellular and intracellular Ca2+ sources. The increased membrane permeability to Ca2+ cannot be attributed to activation of endogenous Ca2+ channels, because responses were unaffected by the potent Ca2+-channel blocker cobalt. Instead, observations that Abeta42 and other oligomers caused rapid cellular leakage of anionic fluorescent dyes point to a generalized increase in membrane permeability. The resulting unregulated flux of ions and molecules may provide a common mechanism for oligomer-mediated toxicity in many amyloidogenic diseases, with dysregulation of Ca2+ ions playing a crucial role because of their strong trans-membrane concentration gradient and involvement in cell dysfunction and death 5.

Islet amyloid in type 2 diabetes, and the toxic oligomer hypothesis: Type 2 diabetes (T2DM) is characterized by insulin resistance, defective insulin secretion, loss of beta-cell mass with increased beta-cell apoptosis and islet amyloid. The islet amyloid is derived from islet amyloid polypeptide (IAPP, amylin), a protein coexpressed and cosecreted with insulin by pancreatic beta-cells. In common with other amyloidogenic proteins, IAPP has the propensity to form membrane permeant toxic oligomers. Accumulating evidence suggests that these toxic oligomers, rather than the extracellular amyloid form of these proteins, are responsible for loss of neurons in neurodegenerative diseases. It has been suggested that formation of intracellular IAPP oligomers may contribute to beta-cell loss in T2DM6.

References
1. Petkova AT, Ishii Y, Balbach JJ, Antzutkin ON, Leapman RD, Delaglio F, Tycko R (2002). A structural model for Alzheimer's ß-amyloid fibrils based on experimental constraints from solid state NMR. PN AS., 99(26):16742–16747.
2. Antzutkin ON, Balbach JJ, Leapman RD, Rizzo NW, Reed J, Tycko R (2000). Multiple quantum solid-state NMR indicates a parallel, not antiparallel, organization of ß-sheets in Alzheimer's ß-amyloid fibrils. PNAS., 97:13045-13050.
3. Balbach JJ, Petkova AT, Oyler NA, Antzutkin ON, Gordon DJ, Meredith SC, Tycko R (2002). Supramolecular Structure in Full-Length Alzheimer's ß-Amyloid Fibrils: Evidence for a Parallel ß-Sheet Organization from Solid-State Nuclear Magnetic Resonance. Biophys. J., 83:1205-1216.
4. Beyreuther K, Bush AI, Dyrks T, Hilbich C, König G, Mönning U, Multhaup G, Prior R, Rumble B, Schubert W (1991). Mechanisms of amyloid deposition in Alzheimer's disease. Ann N Y Acad Sci., 640:129-139.
5. Demuro A, Mina E, Kayed R, Milton SC, Parker I, Glabe CG (2005). Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. J. Biol. Chem., 280(17):17294-17300.
6. Haataja L, Gurlo T, Huang CJ, Butler PC (2008). Islet amyloid in type 2 diabetes, and the toxic oligomer hypothesis. Endocr. Rev., 29(3):303-316.

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