The failure rate for the translation of drugs from animal testing to human treatments remains at over 92%, where it has been for the past few decades. The majority of these failures are due to unexpected toxicity — that is, safety issues revealed in human trials that were not apparent in animal tests — or lack of efficacy. However, the use of more innovative tools, such as organs-on-chips, in the preclinical pipeline for drug testing, has revealed that these tools are more able to predict unexpected safety events prior to clinical trials and so can be used for this, as well as for efficacy testing. Here, we review several disease areas, and consider how the use of animal models has failed to offer effective new treatments. We also make some suggestions as to how the more human-relevant new approach methodologies might be applied to address this.

https://doi.org/10.1177/02611929231157756

Poor Translatability of Biomedical Research Using Animals — A Narrative Review

Induction of autophagy is a prospective approach to the treatment of neurodegeneration. In the recent decade, trehalose attracted special attention. It is an autophagy inducer with negligible adverse effects and is approved for use in humans according to FDA requirements. Trehalose has a therapeutic effect in various experimental models of diseases. This glucose disaccharide with a flexible α-1-1'-glycosidic bond has unique properties: induction of mTOR-independent autophagy (with kinase AMPK as the main target) and a chaperone-like effect on proteins imparting them natural spatial structure. Thus, it can reduce the accumulation of neurotoxic aberrant/misfolded proteins. Trehalose has an anti-inflammatory effect and inhibits detrimental oxidative stress partially owing to the enhancement of endogenous antioxidant defense represented by the Nrf2 protein. The disaccharide activates lysosome and autophagosome biogenesis pathways through the protein factors TFEB and FOXO1. Here we review various mechanisms of the neuroprotective action of trehalose and touch on the possibility of pleiotropic effects. Current knowledge about specific features of trehalose pharmacodynamics is discussed. The neuroprotective effects of trehalose in animal models of major neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases are examined too. Attention is given to translational transition to clinical trials of this drug, especially oral and parenteral routes of administration. Besides, the possibility of enhancing the therapeutic benefit via a combination of mTOR-dependent and mTOR-independent autophagy inducers is analyzed. In general, trehalose appears to be a promising multitarget tool for the inhibition of experimental neurodegeneration and requires thorough investigation of its clinical capabilities. 

Disaccharide trehalose in experimental therapies for neurodegenerative disorders: Molecular targets and translational potential

Characterising Alzheimer’s disease (AD) as a metabolic disorder of the brain is gaining acceptance based on the pathophysiological commonalities between AD and major metabolic disorders. Therefore, metabolic interventions have been explored as a strategy for brain energetic rescue. Amongst these, medium-chain fatty acid (MCFA) supplementations have been reported to rescue the energetic failure in brain cells as well as the cognitive decline in patients. Short-chain fatty acids (SCFA) have also been implicated in AD pathology. Due to the increasing therapeutic interest in metabolic interventions and brain energetic rescue in neurodegenerative disorders, in this review, we first summarise the role of SCFAs and MCFAs in AD. We provide a comparison of the main findings regarding these lipid species in established AD animal models and recently developed human cell-based models of this devastating disorder.

/pdf/fats-friends-or-foes-investigating-the-role-of-short-and-2wdntk6z.pdf

Fats, Friends or Foes: Investigating the Role of Short- and Medium-Chain Fatty Acids in Alzheimer’s Disease

Abstract Background The amyloid- β (A β ) cascade is one of the most studied theories linked to AD. In multiple models, A β accumulation and dyshomeostasis have shown a key role in AD onset, leading to excitatory/inhibitory imbalance, the impairments of synaptic plasticity and oscillatory activity, and memory deficits. Despite the higher prevalence of Alzheimer’s disease (AD) in women compared to men, the possible sex difference is scarcely explored and the information from amyloidosis transgenic mice models is contradictory. Thus, given the lack of data regarding the early stages of amyloidosis in female mice, the aim of this study was to systematically characterize the effect of an intracerebroventricular ( icv. ) injection of A β 1–42 on hippocampal-dependent memory, and on associated activity-dependent synaptic plasticity in the hippocampal CA1–CA3 synapse, in both male and female mice. Methods To do so, we evaluated long term potentiation (LTP) with ex vivo electrophysiological recordings as well as encoding and retrieval of spatial (working, short- and long-term) and exploratory habituation memories using Barnes maze and object location, or open field habituation tasks, respectively. Results A β 1–42 administration impaired all forms of memory evaluated in this work, regardless of sex. This effect was displayed in a long-lasting manner (up to 17 days post-injection). LTP was inhibited at a postsynaptic level, both in males and females, and a long-term depression (LTD) was induced for the same prolonged period, which could underlie memory deficits. Conclusions In conclusion, our results provide further evidence on the shifting of LTP/LTD threshold due to a single icv . A β 1–42 injection, which underly cognitive deficits in the early stages of AD. These long-lasting cognitive and functional alterations in males and females validate this model for the study of early amyloidosis in both sexes, thus offering a solid alternative to the inconsistence of amyloidosis transgenic mice models. 

Systematic characterization of a non-transgenic Aβ1–42 amyloidosis model: synaptic plasticity and memory deficits in female and male mice

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive decline that severely affects patients and their families. Genetic and environmental risk factors, such as viral infections, synergize to accelerate the aging-associated neurodegeneration. Genetic risk factors for late-onset AD (LOAD), which accounts for most AD cases, are predominantly implicated in microglial and immune cell functions. As such, microglia play a major role in formation of amyloid beta (Aβ) plaques, the major pathological hallmark of AD. This review aims to provide an overview of the current knowledge regarding the role of microglia in Aβ plaque formation, as well as their impact on morphological and functional diversity of Aβ plaques. Based on this discussion, we seek to identify challenges and opportunities in this field with potential therapeutic implications. 

Microglia and amyloid plaque formation in Alzheimer's disease – Evidence, possible mechanisms, and future challenges

Alzheimer's disease (AD) constitutes the most prominent form of dementia among elderly individuals worldwide. Disease modeling using murine transgenic mice was first initiated thanks to the discovery of heritable mutations in amyloid precursor protein (APP) and presenilins (PS) genes. However, due to the repeated failure of translational applications from animal models to human patients, along with the recent advances in genetic susceptibility and our current understanding on disease biology, these models have evolved over time in an attempt to better reproduce the complexity of this devastating disease and improve their applicability. In this review, we provide a comprehensive overview about the major pathological elements of human AD (plaques, tauopathy, synaptic damage, neuronal death, neuroinflammation and glial dysfunction), discussing the knowledge that available mouse models have provided about the mechanisms underlying human disease. Moreover, we highlight the pros and cons of current models, and the revolution offered by the concomitant use of transgenic mice and omics technologies that may lead to a more rapid improvement of the present modeling battery. 

/pdf/transgenic-mouse-models-of-alzheimers-disease-an-integrative-1wfxyzdh.pdf

Transgenic Mouse Models of Alzheimer’s Disease: An Integrative Analysis

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Transgenic Mouse Models of Alzheimer’s Disease: An Integrative Analysis