Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
, 38 (9), 1205-1235

Amyloid Beta: Structure, Biology and Structure-Based Therapeutic Development

Affiliations
Review

Amyloid Beta: Structure, Biology and Structure-Based Therapeutic Development

Guo-Fang Chen et al. Acta Pharmacol Sin.

Abstract

Amyloid beta peptide (Aβ) is produced through the proteolytic processing of a transmembrane protein, amyloid precursor protein (APP), by β- and γ-secretases. Aβ accumulation in the brain is proposed to be an early toxic event in the pathogenesis of Alzheimer's disease, which is the most common form of dementia associated with plaques and tangles in the brain. Currently, it is unclear what the physiological and pathological forms of Aβ are and by what mechanism Aβ causes dementia. Moreover, there are no efficient drugs to stop or reverse the progression of Alzheimer's disease. In this paper, we review the structures, biological functions, and neurotoxicity role of Aβ. We also discuss the potential receptors that interact with Aβ and mediate Aβ intake, clearance, and metabolism. Additionally, we summarize the therapeutic developments and recent advances of different strategies for treating Alzheimer's disease. Finally, we will report on the progress in searching for novel, potentially effective agents as well as selected promising strategies for the treatment of Alzheimer's disease. These prospects include agents acting on Aβ, its receptors and tau protein, such as small molecules, vaccines and antibodies against Aβ; inhibitors or modulators of β- and γ-secretase; Aβ-degrading proteases; tau protein inhibitors and vaccines; amyloid dyes and microRNAs.

Figures

Figure 1
Figure 1
Molecular architecture of APP. Schematic representation of human APP isoforms and the APP-like proteins (APLP), APLP1 and APLP2. APP isoforms range in size from 695 to 770 amino acids. The most abundant form in brain is APP695, which lacks a Kunitz type protease inhibitor sequence in its ectodomain. APP751 and APP770 contain the Kunitz type serine protease inhibitory domain (KPI) are mainly expressed on the surface of peripheral cells and platelets.
Figure 2
Figure 2
Human APP proteolytic pathways. Human APP proteolysis in the non-amyloidogenic pathway and amyloidogenic pathway. Non-amyloidogenic processing of APP refers to the sequential processing of APP by membrane bound α-secretases, which cleave within the Aβ domain to generate the membrane-tethered α-C terminal fragment CTFα (C83) and the N-terminal fragment sAPPα. CTFα is then cleaved by γ-secretases to generate extracellular P3 and the APP intracellular domain (AICD). Amyloidogenic processing of APP is carried out by the sequential action of membrane bound β- and γ-secretases. β-Secretase cleaves APP into the membrane-tethered C-terminal fragments β (CTFβ or C99) and N-terminal sAPPβ. CTFβ is subsequently cleaved by γ-secretases into the extracellular Aβ and APP intracellular domain (AICD).
Figure 3
Figure 3
Structures of Aβ monomer, fibril and oligomers. (A) The primary amino acid sequence of the 42 amino acid Aβ isoform Aβ42. Aβ encompasses a group of peptides ranging in size from 37–49 residues. (B) The structure of amyloid beta peptide (1–28), which forms a predominately alpha-helical structure that can be converted to a beta-sheet structure in membrane-like media (PDB code: 1AMC, 1AMB), it's the major proteinaceous component of amyloid deposits in Alzheimer's disease. The side chains of histidine-13 and lysine-16 residing on the same face of the helix are close. (C) Solution structure of amyloid beta peptide (1–40), in which the C-terminal two-thirds of the peptide form an alpha-helix conformation between residues 15 and 36 with a kink or hinge at 25–27 in aqueous sodium dodecyl sulfate (SDS) micelles with a bend centered at residue 12, while the peptide is unstructured between residues 1 and 14 which are mainly polar and likely solvated by water (PDB code: 1BA4, 1BA6) . It collapsed into a compact series of loops, strands, and turns with no alpha-helical or beta-sheet structure. The van der Waals and electrostatic forces maintain its conformational stabilization. Approximately 25% of the surface is uninterrupted hydrophobic, and the compact coil structure is meta-stabled, which may lead to a global conformational rearrangement and formation of intermolecular beta-sheet secondary structure caused by fibrillization. (D) Amyloid beta peptide (10–35) forms a collapsed coil structure (PDB code: 1HZ3). It collapsed into a compact series of loops, strands, and turns with no alpha-helical or beta-sheet structure. The van der Waals and electrostatic forces maintain its conformational stabilization. Approximately 25% of the surface is uninterrupted hydrophobic, and the compact coil structure is meta-stabled, which may lead to a global conformational rearrangement and formation of intermolecular beta-sheet secondary structure caused by fibrillization. (E) Proposed pathway for the conversion of amyloid beta monomers to higher order oligomers, protofibrils and fibrils. Aβ monomers can form higher order assemblies ranging from low molecular weight oligomers, including dimers, trimers, tetramers, and pentamers, to mid-range molecular weight oligomers including hexamers, nonamers and dodecamers to protofibrils and fibrils.
Figure 4
Figure 4
Biological functions of Aβ. Aβ monomers can form higher order assemblies ranging from low molecular weight oligomers (including dimers, trimers, tetramers, and pentamers) to midrange-molecular weight oligomers, high molecular weight oligomers, protofibrils fibrils and senile plaques. Soluble Aβ can interact with potential receptors and activate downstream pathways to generate reactive oxygen species, hyperphosphorylate Tau protein, and cause inflammatory responses, which may result in neuronal death and lead to Alzheimer's disease.
Figure 5
Figure 5
Aβ homeostasis involves production, aggregation, transport, degradation, and clearance. Aβ is produced in peripheral tissues and the CNS, where it can aggregate and form insoluble fibrils. Soluble Aβ can be transported across the BBB from blood to brain via RAGE, and from brain to blood via LRP. Aβ can also bind to transport proteins, eg., apoE, apoJ, α2-macroglobulin (α2M), which may influence Aβ sequestration as well as the form of its accumulation in brain. Aβ can be proteolytically degraded by the proteases Neprilysin (Nep), endothelin converting enzymes (ECE), insulin degrading enzyme (IDE), plasmin and other Aβ-degrading proteases (MMP, Cathepsin D), as well as by microglia-mediated degradation.

Similar articles

See all similar articles

Cited by 22 PubMed Central articles

See all "Cited by" articles

MeSH terms

Feedback