Amyloid plaques beyond Aβ: a survey of the diverse modulators of amyloid aggregation

Abstract

Aggregation of the amyloid-β (Aβ) peptide is strongly correlated with Alzheimer’s disease (AD). Recent research has improved our understanding of the kinetics of amyloid fibril assembly and revealed new details regarding different stages in plaque formation. Presently, interest is turning toward studying this process in a holistic context, focusing on cellular components which interact with the Aβ peptide at various junctures during aggregation, from monomer to cross-β amyloid fibrils. However, even in isolation, a multitude of factors including protein purity, pH, salt content, and agitation affect Aβ fibril formation and deposition, often producing complicated and conflicting results. The failure of numerous inhibitors in clinical trials for AD suggests that a detailed examination of the complex interactions that occur during plaque formation, including binding of carbohydrates, lipids, nucleic acids, and metal ions, is important for understanding the diversity of manifestations of the disease. Unraveling how a variety of key macromolecular modulators interact with the Aβ peptide and change its aggregation properties may provide opportunities for developing therapies. Since no protein acts in isolation, the interplay of these diverse molecules may differentiate disease onset, progression, and severity, and thus are worth careful consideration.

Role of the N-terminus for the stability of an amyloid-β fibril with three-fold symmetry

“…Hallmark of AD is the aggregation of amyloid-β (Aβ) monomers to oligomers, fibrils and finally plaques as explained by the Aβ cascade hypothesis [3–5]. From extensive experimental work it is known, that Aβ peptide's aggregation behavior is influenced by many external and internal factors like pH-value, temperature, ionic strength, peptide length, or point mutations [6–12]. …”

What Is the “Relevant” Amyloid β42 Concentration?

“…Quantitative postmortem analyses of patient-derived senile plaques revealed Ab (40 and 42) to be their predominant components, [2] but also showedaremarkable heterogeneity of the deposits;a dditional plaque constituents includingd iversep roteins and peptides, [2b, 4] lipids, [5] RNA, carbohydrates, and various metal ions. [3] As ar esult, the Ab42 concentration in as enile plaque is expectedt ob es omewhat lower than 221.5 mm,b ut certainly still in the high-mm range. In consequence of ar ecent paradigm shift, Ab fibrillard eposits are no longerc onsidered to be the culprit of AD, but instead benign, possibly even protective, which is likely ac onsequence of fibril-borne Ab42 being packaged into ar elatively inert state with very low biological activity.…”

“…The highest concentration of Aβ42 in the human brain is found in senile plaques, where the peptide is packed into a dense composite of Aβ fibrils, as well as other biomolecules . As the hypothetical upper boundary of physiologically relevant Aβ42 concentration, the fibrillary state appears reasonable, although plaque heterogeneity will produce somewhat lower values (vide infra).…”

“…Assuming a fibril density of ≈1 g mL −1 (i.e., similar to water, although likely slightly higher, as fibrils do sediment slowly in water), this yields a concentration of 221.5 m m (i.e., 221.5 mmol L −1 ) Aβ42 “monomer‐in‐fibril”. Quantitative postmortem analyses of patient‐derived senile plaques revealed Aβ (40 and 42) to be their predominant components, but also showed a remarkable heterogeneity of the deposits; additional plaque constituents including diverse proteins and peptides, lipids, RNA, carbohydrates, and various metal ions . As a result, the Aβ42 concentration in a senile plaque is expected to be somewhat lower than 221.5 m m , but certainly still in the high‐m m range.…”

“…1 The highest concentration of Ab42 in the human brain is found in senile plaques, [2] where the peptide is packed into a dense composite of Ab fibrils, as well as other biomolecules. [3] As the hypothetical upper boundary of physiologicallyr elevant Ab42 concentration, the fibrillary state appearsr easonable, althoughp laqueh eterogeneity will produce somewhat lower values (vide infra). Ab42 has am olar mass of 4514 gmol À1 .A ssuming af ibril density of % 1gmL À1 (i.e.,s imilart ow ater, althoughl ikely slightly higher,a sf ibrils do sediment slowly in water), this yields ac oncentrationo f2 21.5 mm (i.e., 221.5 mmol L À1 )A b42 "monomer-in-fibril".…”