Extracellular protein components of amyloid plaques and their roles in Alzheimer's disease pathology

Abstract

Alzheimer's disease (AD) is pathologically defined by the presence of fibrillar amyloid β (Aβ) peptide in extracellular senile plaques and tau filaments in intracellular neurofibrillary tangles. Extensive research has focused on understanding the assembly mechanisms and neurotoxic effects of Aβ during the last decades but still we only have a brief understanding of the disease associated biological processes. This review highlights the many other constituents that, beside Aβ, are accumulated in the plaques, with the focus on extracellular proteins. All living organisms rely on a delicate network of protein functionality. Deposition of significant amounts of certain proteins in insoluble inclusions will unquestionably lead to disturbances in the network, which may contribute to AD and copathology. This paper provide a comprehensive overview of extracellular proteins that have been shown to interact with Aβ and a discussion of their potential roles in AD pathology. Methods that can expand the knowledge about how the proteins are incorporated in plaques are described. Top-down methods to analyze post-mortem tissue and bottom-up approaches with the potential to provide molecular insights on the organization of plaque-like particles are compared. Finally, a network analysis of Aβ-interacting partners with enriched functional and structural key words is presented.

Keywords: Alzheimer’s disease; Amyloid corona; Amyloid-β; Protein interaction network; Senile plaque.

Fig. 1

Extracellular senile plaques are pathological hallmarks of AD brains. The plaques are proteinaceous deposits with Aβ as main constituent but also containing a range of other components

Fig. 2

Approaches to explore the composition and organization of senile plaques. (A) Top-down methods starts from plaque tissue samples and analyze the plaque structure by e.g. microscopy or mass-spectrometry proteomics. (B) Bottom-up methods make use of in vitro models in order to study composition, protein structure and interactions from a molecular perspective. The amyloid corona refers to the layer of proteins from a biological fluid that is sequestered by the amyloid fibrils

Fig. 3

STRING protein network analysis of the proteins in Table 1 (except immunoglobulins). The nodes are colored based on the functional classification used in the article and the thickness of the connecting lines show the confidence of the association

Fig. 4

Functional and structural enrichment in the STRING network. The bar diagrams show the –log₁₀ of the false discovery rate for the 10 most enriched keywords from each category

Fig. 5

Illustration of how extracellular and intracellular components may end up in senile plaques. Most of the produced Aβ are secreted and can under certain circumstances aggregate in the extracellular environment. The amyloid will bind to extracellular components to form multicomponent aggregates. Amyloid deposits can also trigger cellular response through cell surface receptors leading to phagocytosis and co-accumulation of intracellular components. In another route, the extracellular amyloid can promote the formation of oligomeric Aβ. These oligomers, as well as Aβ monomers, can be internalized by cells and accumulate in the intracellular environment. Too high intracellular load of aggregated proteins may eventually lead to cell death and release of the aggregated material