The amyloid core

A better understanding of the biochemical nature of the amyloid core of the NP was only gained decades after its initial description. In 1984, it was discovered that boiling the plaque cores in formic acid could dissociate them, revealing that they were proteinaceous in nature and composed primarily of the Ap peptide [3]. 

Antibodies raised against the Ap peptide were subsequently used to identify more diffuse types of Ap-containing deposits in AD brain by immunohistochemistry. Diffuse Ap peptide deposits lack the 

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Balguerie, A., Dos Reis, S., Coulary-Salin, B., Chaignepain, S., Sabourin, M., Schmitter, J. M., and Saupe, S.J. (2004). The sequences appended to the amyloid core region of the HET-s prion protein determine higher-order aggregate organization in vivo. J. Cell Sci. 117, 2599-2610. 

The mechanism of AD pathogenesis still remains unclear. However, one mechanism, amyloid (3 (A(3) accumulation, may be due to the disturbance in metal homeostasis in AD brains [Strausak et al., 2001]. A(3 peptides are the major constituents of the amyloid core of senile plaques, which are derived from the amyloid precursor protein (APP) and are secreted into extracelluar spaces. Both APP and A(3 contain a copper-binding domain [Hesse et al., 1994 Atwood et al., 1998]. High concentrations of copper, zinc, and iron have been found within the amyloid deposits in AD brains [Lovell et al., 1998], A(3 peptides can be rapidly precipitated by copper under mildly acidic conditions and by zinc at low physiological (submicromolar) concentrations [Bush et al., 1994], An age-dependent binding between A(3 peptides with excess brain metals (copper, iron, and zinc) induces A(3 peptides to precipitate into metal-enriched plaques [Bush, 2002],... 

The amyloid cores were strongly immunoreactive with antisera to the mid-region of the molecule, and the periphery of the cores was immunostained by antibodies to N- or C-terminal domains. In addition, the antisera to PrP labeled large areas of tbe neuropil that did not show the tinctorial and optical properties of amyloid, suggesting that amyloid deposition in GSS is accompanied by accumulation of PrP peptides, which are not assembled into amyloid fibrils. 

The way that Pn peptides self-assemble is important for polypeptides and proteins amyloid-type structures are believed to have the same core stmcture, and in fact the propensity to self-assemble in this manner is hypothesized to be a general property of polypeptides [52]. It is therefore unsurprising that systems featuring this motif are common. In recent years, a push towards the use of peptide-based self-assembled materials has led to increasing interest in extending their functionality by derivatising them. 

Fig. 4. New structural models for amyloid and prion filaments with the parallel and in-register arrangement of //-strands in the //-sheets. //-Strands are denoted by arrows. The filaments are formed by hydrogen-bonded stacks of repetitive units. Axial projections of single repetitive units corresponding to each model are shown on the top. Lateral views of the overall structures are on the bottom. (A) The core of a //-helical model of the //-amyloid protofilament (Petkova et al., 2002). Two such protofilaments coil around one another to form a //-amyloid fibril. (B) The core of a //-helical model of the HET-s prion fibril (Ritter et al., 2005). The repetitive unit consists of two //-helical coils. (C) The core of a superpleated //-structura l model suggested for yeast prion Ure2p protofilaments and other amyloids (Kajava et al., 2004).

Amyloid fibrils form from a variety of native proteins with diverse sequences and folds. The classic method for the structural analysis of amyloid has been X-ray fiber diffraction amyloid fibrils exhibit a characteristic diffraction signature, called the cross-/) pattern. This cross-/ pattern suggested a repeating structure in which /1-sheets run parallel to the fiber axis with their constituent /1-strands perpendicular to that direction (Sunde and Blake, 1997). This diffraction signature pointed to an underlying common core molecular structure for the amyloid fibril that could accommodate diverse sequences and folds. A number of groups have proposed amyloid folds that are consistent with the experimental data and these can be linked to repeating /1-structured units. 

Inouye, H., and Kirschner, D. A. (1996). Refined fibril structures The hydrophobic core in Alzheimer s amyloid /1-protein and prion as revealed by X-ray diffraction. Ciba Found. Symp. 199, 22-35 discussion 35-9. 

Fig. 1. Cross-/] structure of amyloid fibrils. (A) Cartoon representation of a cross-/] X-ray diffraction pattern. The defining features are a meridional reflection at 4.7 A and an equatorial reflection on the order of 10 A. The 4.7-A reflection is generally much brighter and sharper than the reflection at 10 A. (B) The cross-/] core structure of amyloid fibrils. Parallel /(-sheets are depicted, but the structure could equivalendy be composed of antiparallel /(-sheets or a mix of parallel and antiparallel. The 4.7-A spacing of /(-strands within each /(-sheet is parallel to the long fibril axis. The depicted 10-A sheet-to-sheet spacing actually ranges from about 5 to 14 A (Fandrich and Dobson, 2002), depending on the size and packing of amino acid side chains. Amyloid fibrils have diameters on the order of 100 A.

The notion of a common core structure has been further supported by synchrotron X-ray fiber diffraction patterns of several amyloid fibrils the patterns show common reflections in addition to those at 4.7 and 10 A (Sunde et al., 1997). Although these data give some insight into the arrangement of the amyloid fibril core, the exact molecular structure and organization of the proteins making up this common core have yet to be uniquely defined. The inherently noncrystalline, insoluble nature of the fibrils makes their structures difficult to study via traditional techniques of X-ray crystallography and solution NMR. An impressive breadth of biochemical and biophysical techniques has therefore been employed to illuminate additional features of amyloid fibril structure. 

Roher AE, Lowenson JD, Clarke S, Wolkow C, Wang R, Cotter RJ, Reardon IM, Ziircher-Neely HA, Heinrikson RL, Ball MJ, Greenberg B. (1993) Structural alterations in the peptide backbone of beta-amyloid core protein may account for its deposition and stability in Alzheimer s disease. J Biol Chem268 3072-3083. 

Solanezumab is a monoclonal antibody raised against Ap13 28, recognizing an epitope in the core of the amyloid peptide, binding selectively to soluble Ap and with low affinity for the fAp form... 

The NR data revealed that the protein fully inserts into the hydrophobic core, disrupting both hpid leaflets but does not lead to significant disruphon of the head group region as determined by the absence of increased water content in the SLD profiles. This information was vital for explaining the results of ex situ impedance spectroscopy and modeling the increased ion transport capabilities of the supported membranes in the presence of amyloid [3-pephdes. 

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