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Compounds targeted for the treatment of Alzheimer's Disease (AD) have consistently failed in clinical trials despite evidence for target engagement and pharmacodynamic activity. This questions the relevance of compounds acting at current AD drug targets - the majority of which reflect the seminal amyloid and, to a far lesser extent, tau hypotheses - and limitations in understanding AD causality as distinct from general dementia. The preeminence of amyloid and tau led to many alternative approaches to AD therapeutics being ignored or underfunded to the extent that their causal versus contributory role in AD remains unknown. These include: neuronal network dysfunction; cerebrovascular disease; chronic, local or systemic inflammation involving the innate immune system; infectious agents including herpes virus and prion proteins; neurotoxic protein accumulation associated with sleep deprivation, circadian rhythm and glymphatic/meningeal lymphatic system and blood-brain-barrier dysfunction; metabolic related diseases including diabetes, obesity hypertension and hypocholesterolemia; mitochondrial dysfunction and environmental factors. As AD has become increasingly recognized as a multifactorial syndrome, a single treatment paradigm is unlikely to work in all patients. However, the biomarkers required to diagnose patients and parse them into mechanism/disease-based sub-groups remain rudimentary and unvalidated as do non-amyloid, non-tau translational animal models. The social and economic impact of AD is also discussed in the context of new FDA regulatory draft guidance and a proposed biomarker-based Framework (re)-defining AD and its stages as part of the larger landscape of treating dementia via the 2013 G8 initiative to identify a disease-modifying therapy for dementia/AD by 2025., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Many chronic human diseases, including multiple neurodegenerative diseases, are associated with deleterious protein aggregates, also called protein amyloids. One common therapeutic strategy is to develop protein aggregation inhibitors that can slow down, prevent, or remodel toxic amyloids. Natural products are a major class of amyloid inhibitors, and several dozens of natural product-based amyloid inhibitors have been identified and characterized in recent years. These plant- or microorganism-extracted compounds have shown significant therapeutic potential from in vitro studies as well as in vivo animal tests. Despite the technical challenges of intrinsic disordered or partially unfolded amyloid proteins that are less amenable to characterizations by structural biology, a significant amount of research has been performed, yielding biochemical and pharmacological insights into how inhibitors function. This review aims to summarize recent progress in natural product-based amyloid inhibitors and to analyze their mechanisms of inhibition in vitro. Major classes of natural product inhibitors and how they were identified are described. Our analyses comprehensively address the molecular interactions between the inhibitors and relevant amyloidogenic proteins. These interactions are delineated at molecular and atomic levels, which include covalent, non-covalent, and metal-mediated mechanisms. In vivo animal studies and clinical trials have been summarized as an extension. To enhance natural product bioavailability in vivo, emerging work using nanocarriers for delivery has also been described. Finally, issues and challenges as well as future development of such inhibitors are envisioned., (Copyright © 2017 Elsevier Inc. All rights reserved.)