The role of β-Amyloid Peptides in Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative disease and the most common cause of dementia. AD is characterised by progressive cognitive decline and memory dysfunction.   The two major histopathological lesions in AD are senile plaques composed of diverse beta-amyloid (Aβ) peptide aggregates and neurofibrillary tangles composed of tau proteins aggregates.  The dysregulation of Aβ production, folding, clearance and degradation result in the accumulation of Aβ and formation of senile plaques.  However, the correlation between Aβ plaques density and the severity of AD is ambiguous. Studies show that elevated levels of Aβ, oligomeric Aβ and protofibrils can induce calcium dyshomeostasis, trigger activation of caspase 3, or regulate a variety of signalling cascades (such as NMDARs and AMPARs) which lead to synapse dysfunction, shrinkage, collapse and neuronal cell death. It has been suggested that soluble nonfibrillar intermediates are the initiators of AD, whereas mature fibril formation represent the later stages of AD pathology.

Amyloid precursor protein (APP) is sequentially cleaved by β- and γ-secretase to form Aβ peptides. β-secretase cleaves APP to release soluble APPβ and exposes a membrane bound C-terminal fragment (CTF99). Intramembrane proteolysis of CTF99 by γ-secretase initially occurs at various ε-cleavage sites, followed by carboxypeptidase cleavage at γ-cleavage sites to produce 39-43 amino acid Aβ peptide fragments. Aβ (1-40) is the most abundant form followed by Aβ (1-42). Aβ peptides undergo a conformation switch from α-helical to β-sheet structure. The Aβ β-sheets can adopt parallel or anti-parallel arrangements within protofilaments depending on the peptide properties. The β-sheet content is linked to Aβ insolubility. The longer forms of Aβ are more hydrophobic and fibrillogenic. Aβ (1-42) has been identified as the major component in senile plaques. An increase in Aβ (1-42) to Aβ (1-40) ratio has been shown to increase the propensity for Aβ aggregation. The fibrillar state has also been shown to be associated with protease resistance. The solubility and composition of Aβ species in different populations of amyloid deposits correlates to the disease state of the patient.

Synthetic Aβ peptides are widely used to examine the structure, assembly and the activity of Aβ monomers, soluble oligomers and insoluble fibrils. Aβ peptides provide a means to assess the dynamics of nucleation and elongation of homogeneous and heterogeneous Aβ fibrils under various physiological conditions. Studies using Aβ peptides and their truncated variants provide an insight into biophysical properties and fibrillogenic regions and help identify intermediate species that contribute to Aβ toxicity. Furthermore, Aβ peptides are subject to post-translational modifications, such as oxidation, phosphorylation, isomerisation, nitration and glycosylation, which exhibit different physiological and pathological properties. Understanding the effects of various modifications will help establish factors that influence Aβ amyloidogenicity.

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