A Tau-Driven Adverse Outcome Pathway Blueprint Toward Memory Loss in Sporadic (Late-Onset) Alzheimer’s Disease with Plausible Molecular Initiating Event Plug-Ins for Environmental Neurotoxicants

Abstract

The worldwide prevalence of sporadic (late-onset) Alzheimer’s disease (sAD) is dramatically increasing. Aging and genetics are important risk factors, but systemic and environmental factors contribute to this risk in a still poorly understood way. Within the frame of BioMed21, the Adverse Outcome Pathway (AOP) concept for toxicology was recommended as a tool for enhancing human disease research and accelerating translation of data into human applications. Its potential to capture biological knowledge and to increase mechanistic understanding about human diseases has been substantiated since. In pursuit of the tau-cascade hypothesis, a tau-driven AOP blueprint toward the adverse outcome of memory loss is proposed. Sequences of key events and plausible key event relationships, triggered by the bidirectional relationship between brain cholesterol and glucose dysmetabolism, and contributing to memory loss are captured. To portray how environmental factors may contribute to sAD progression, information on chemicals and drugs, that experimentally or epidemiologically associate with the risk of AD and mechanistically link to sAD progression, are mapped on this AOP. The evidence suggests that chemicals may accelerate disease progression by plugging into sAD relevant processes. The proposed AOP is a simplified framework of key events and plausible key event relationships representing one specific aspect of sAD pathology, and an attempt to portray chemical interference. Other sAD-related AOPs (e.g., Aβ-driven AOP) and a better understanding of the impact of aging and genetic polymorphism are needed to further expand our mechanistic understanding of early AD pathology and the potential impact of environmental and systemic risk factors.

Building a Network of Adverse Outcome Pathways (AOPs) Incorporating the Tau-Driven AOP Toward Memory Loss (AOP429)

“…This network is assembled of individual AOPs, available in AOP-wiki, sharing one or more events at molecular, cellular or organism level. Plausible molecular initiating events (MIEs) plugged into this tau-driven AOP are depicted by possible molecular targets of the environmental neurotoxicants [ 10 ]. The dotted lines indicate indirect links between the source and the target.…”

“… Schematic representation of the proposed tau-driven AOP for memory loss, presenting a starting point (bidirectional relationship between glucose and cholesterol metabolism) which can trigger a cascade of key events (KEs) (mitochondrial dysfunction, oxidative stress, hyperphosphorylated tau, dysfunctional autophagy, toxic tau oligomers, dysfunctional axonal transport, dysfunctional synapses, neuroinflammation, and neuronal dysfunction), which eventually can lead to the adverse outcome (AO), memory loss (modified from [ 10 ]). …”

“…Recently, a tau-driven AOP for the memory loss in sporadic (late-onset) Alzheimer’s disease (sAD) has been proposed [ 10 ]. In this AOP blueprint, several environmental neurotoxicants were also suggested as plausible MIE plug-ins, portraying possible chemical interference with early sAD pathology.…”

“…In more detail, 27 tentative MIEs triggered by different stressors, including environmental chemicals and drugs, were plugged into the proposed processes of the tau-driven AOP under development (AOP429). It was hypothesized that neurotoxicity and sAD pathology may share common pathological processes [ 10 ]. Next, this hypothesis was further confirmed by identifying microRNA (miR)-gene interactions commonly regulated by the processes described in this tau-driven AOP [ 11 ].…”

The Adverse Outcome Pathway Framework Applied to Neurological Symptoms of COVID-19

“…Breaking down complex biological pathways into linear constructs and reassembling them into AOP networks can provide mechanistic understanding based on the available biological and toxicological evidence [ 18 , 19 , 20 ]. Due to its fundamental conceptual principles and guidelines, it is beginning to be applied also within the biomedical field [ 21 ].…”