MODELS OF AMYLOID SEEDING IN ALZHEIMER'S DISEASE AND SCRAPIE: Mechanistic Truths and Physiological Consequences of the Time-Dependent Solubility of Amyloid Proteins

Abstract

Ordered protein aggregation in the brain is a hallmark of Alzheimer's disease and scrapie. The disease-specific amyloid fibrils comprise primarily a single protein, amyloid beta, in Alzheimer's disease, and the prion protein in scrapie. These proteins can be induced to form aggregates in vitro that are indistinguishable from brain-derived fibrils. Consequently, much effort has been invested in the development of in vitro model systems to study the details of the aggregation processes and the effects of endogenous molecules that have been implicated in disease. Selected studies of this type are reviewed herein. A simple mechanistic model has emerged for both processes that involves a nucleation-dependent polymerization. This mechanism dictates that aggregation is dependent on protein concentration and time. Furthermore, amyloid formation can be seeded by a preformed fibril. The physiological consequences of this mechanism are discussed.

Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity

“…Protein aggregation is a common hallmark of neurodegenerative disease (Harper & Lansbury, 1997; Trojanowski et al , 1998; Koo et al , 1999; Aguzzi & O'Connor, 2010) although the mechanisms of toxicity remain poorly understood. Different neurodegenerative diseases, or their subtypes, are often distinguished by the specific patterns of protein aggregation.…”

Ganglioside‐induced amyloid formation by human islet amyloid polypeptide in lipid rafts

“…The misfolding of a unique peptide or protein into b-sheet-rich fibrous structures is proposed to be a key step in the onset and development of these diseases [3,5]. The amyloid deposits cause cell dysfunction, death, and subsequently severe impairment in tissues of patients.…”

Acceleration of α‐synuclein aggregation by homologous peptides

“…Some studies concentrated on the central sequence of Ab peptide, suggesting that Ab [14][15][16][17][18][19][20][21][22][23] [12] and Ab [16][17][18][19][20][21][22] [13] are the fibril-generating peptide fragments, other study indicated that the Ab 36-42 fragment could form very stable fibril with highly ordered structure and is a key factor determining the aggregation of Ab 1-42 [14]. This renders us to reconsider why only Ab 40 and Ab 42 peptides are neurotoxic and why Ab 42 aggregates into fibrils faster than Ab 40 [5]. a-Syn is another amyloidogenic protein of great interest that is closely associated with the Lewy bodies in Parkinson disease [15,16].…”