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.

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

Copper Homeostasis and Neurodegenerative Disorders (Alzheimer's, Prion, and Parkinson's Diseases and Amyotrophic Lateral Sclerosis)

The discovery of the first neurotransmitter — acetylcholine — was soon followed by the discovery of its hydrolysing enzyme, acetylcholinesterase. The role of acetylcholinesterase in terminating acetylcholine-mediated neurotransmission made it the focus of intense research for much of the past century. But the complexity of acetylcholinesterase gene regulation and recent evidence for some of the long-suspected 'non-classical' actions of this enzyme have more recently driven a profound revolution in acetylcholinesterase research. Although our understanding of the additional roles of acetylcholinesterase is incomplete, the time is ripe to summarize the evidence on a remarkable diversity of acetylcholinesterase functions.

Acetylcholinesterase New roles for an old actor

Acetylcholinesterase Accelerates Assembly of Amyloid-β-Peptides into Alzheimer's Fibrils: Possible Role of the Peripheral Site of the Enzyme

Our understanding of the pathogenesis of diseases has advanced enormously in recent decades. As a consequence, drug discovery has gradually shifted from an entirely humanphenotype-based endeavor to today’s reductionist approach centered on single molecular targets. The focus has shifted from the early animal models to isolated proteins via cellular models. This change has led to a decrease in complexity but also to a decrease in relevance to the human condition. In this context, drug research has become (and still is) aimed mainly at the discovery of small molecules able to modulate the biological function of a single protein target thought to be fully responsible for a certain disease. Much effort has been devoted to achieving selectivity for that given target, and indeed, nowadays, many ligands endowed with outstanding in vitro selectivity are available. This one-molecule, one-target paradigm has led to the discovery of many successful drugs, and it will probably remain a milestone for years to come. However, it should be noted that a highly selective ligand for a given target does not always result in a clinically efficacious drug. This may be because (a) the ligand does not recognize the target in vivo, (b) the ligand does not reach the site of action, or (c) the interaction with the respective target does not have enough impact on the diseased system to restore it effectively. Reasons for the latter might lie in both the multifactorial nature of many diseases and the fact that cells can often find ways to compensate for a protein whose activity is affected by a drug, by taking advantage of the redundancy of the system, i.e., of the existence of parallel pathways. Medicinal chemists are often faced with these frustrating aspects of drug research. Drawbacks a and b can be addressed through the well-established rational ligand modification approaches. But issue c is more problematic and needs to be carefully discussed. This is one of the aims of the present article.

https://pubs.acs.org/doi/pdf/10.1021/jm800210c

Multi-Target-Directed Ligands To Combat Neurodegenerative Diseases

Acetylcholinesterase, a senile plaque component, affects the fibrillogenesis of amyloid-β-peptides

Chlorophenols may be present in soils by land application of biocides or chlorophenol- and chloroguaiacol-containing sludges from pulp bleaching effluent treatment. Polychlorophenols like 2,4,5-trichlorophenol (2,4,5-TCP) are priority pollutants resistant to biodegradation. In this work, the mineralization (14CO2 evolution) of [U-14C-2,4,5]-TCP in soil not previously exposed to chloroorganics was studied. After 60 days of incubation, soil mineralized 15−45% of 2,4,5-TCP when it was exposed to 1, 10, or 100 ppm of this compound. Minimal half-lives for 2,4,5-TCP of 35−170 days were estimated. Less than 2% of mineralization was observed in soil exposed to 500 ppm or in incubations with sterile soil spiked with 10 or 100 ppm of 2,4,5-TCP. Thirty days of preincubation of soil with 10 or 100 ppm of 2,4,5-TCP increased the rate of mineralization of an additional amount of this pollutant. On the other hand, the presence of a mixture of chloroguaiacols decreased the mineralization of trichlorophenol in this soil. ...

Microbial mineralization of 2,4,5-trichlorophenol in soil

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Acetylcholinesterase Accelerates Assembly of Amyloid-β-Peptides into Alzheimer's Fibrils: Possible Role of the Peripheral Site of the Enzyme

Acetylcholinesterase, a senile plaque component, affects the fibrillogenesis of amyloid-β-peptides

Microbial mineralization of 2,4,5-trichlorophenol in soil