Poor Translatability of Biomedical Research Using Animals — A Narrative Review

Alternatives to Laboratory Animals, Journal Year: 2023, Volume and Issue: 51(2), P. 102 - 135

Published: March 1, 2023

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

Language: Английский

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

Journal of Neuroimmunology, Journal Year: 2024, Volume and Issue: 390, P. 578342 - 578342

Published: April 5, 2024

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

Language: Английский

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Immune Activation in Alzheimer Disease

Annual Review of Immunology, Journal Year: 2024, Volume and Issue: 42(1), P. 585 - 613

Published: March 1, 2024

Alzheimer disease (AD) is the most common neurodegenerative disease, and with no efficient curative treatment available, its medical, social, economic burdens are expected to dramatically increase. AD historically characterized by amyloid β (Aβ) plaques tau neurofibrillary tangles, but over last 25 years chronic immune activation has been identified as an important factor contributing pathogenesis. In this article, we review recent advances in our understanding of significance development AD. We describe how brain-resident macrophages, microglia, able detect Aβ species be activated, well consequences activated microglia discuss transcriptional changes AD, their unique heterogeneity humans, emerging strategies study human microglia. Finally, expose, beyond role peripheral signals different cell types activation.

Language: Английский

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Behaviour Hallmarks in Alzheimer’s Disease 5xFAD Mouse Model

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(12), P. 6766 - 6766

Published: June 20, 2024

The 5xFAD transgenic mouse model widely used in Alzheimer’s disease (AD) research recapitulates many AD-related phenotypes with a relatively early onset and aggressive age-dependent progression. Besides developing amyloid peptide deposits alongside neuroinflammation by the age of 2 months, as well exhibiting neuronal decline 4 months that intensifies 9 these mice manifest broad spectrum behavioural impairments. In this review, we present extensive repertoire dysfunctions mice, organised into four categories: motor skills, sensory function, learning memory abilities, neuropsychiatric-like symptoms. problems, associated agility reflex movements, balance coordination, skeletal muscle typically arise time reach age. function (such taste, smell, hearing, vision) starts to deteriorate when buildups spread related anatomical structures. cognitive functions, encompassing such visual recognition, associative, spatial working, reference learning, show signs from 6 Concerning symptoms, comprising apathy, anxiety depression, willingness for exploratory behaviour, it is believed motivational changes emerge approximately Unfortunately, numerous studies different laboratories are often contradictory on conclusions drawn identification age, making preclinical rodent models not easily translatable humans. This variability likely due range factors animals themselves, housing husbandry conditions, experimental settings. forthcoming studies, greater clarity details conducting testing could minimise inconsistencies ensure reliability reproducibility results.

Language: Английский

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

Pharmacological Research, Journal Year: 2022, Volume and Issue: 183, P. 106373 - 106373

Published: July 28, 2022

Language: Английский

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Vulnerability of the Hippocampus to Insults: Links to Blood–Brain Barrier Dysfunction

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(4), P. 1991 - 1991

Published: Feb. 6, 2024

The hippocampus is a critical brain substrate for learning and memory; events that harm the can seriously impair mental behavioral functioning. Hippocampal pathophysiologies have been identified as potential causes effects of remarkably diverse array medical diseases, psychological disorders, environmental sources damage. It may be more vulnerable than other areas to insults are related these conditions. One purpose this review assess vulnerability most prevalent types in multiple biomedical domains (i.e., neuroactive pathogens, neurotoxins, neurological conditions, trauma, aging, neurodegenerative disease, acquired injury, health endocrine developmental disabilities, nutrition) evaluate whether affect first prominently compared loci. A second consider role hippocampal blood–brain barrier (BBB) breakdown either causing or worsening harmful each insult. Recent research suggests BBB fragile also prone disruption transport mechanisms act maintain internal milieu. Moreover, compromised could factor common many different insults. Our analysis indicates parts brain, developing interventions protect help prevent ameliorate on memory cognition.

Language: Английский

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Insights on the Use of Transgenic Mice Models in Alzheimer’s Disease Research

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(5), P. 2805 - 2805

Published: Feb. 28, 2024

Alzheimer’s disease (AD), the leading cause of dementia, presents a significant global health challenge with no known cure to date. Central our understanding AD pathogenesis is β-amyloid cascade hypothesis, which underlies drug research and discovery efforts. Despite extensive studies, animal models have completely validated this hypothesis. Effective are essential for accurately replicating key pathological features disease, notably formation plaques neurofibrillary tangles. These markers primarily driven by mutations in amyloid precursor protein (APP) presenilin 1 (PS1) genes familial (FAD) tau tangle pathology. Transgenic mice been instrumental research, heavily relying on overexpression mutated APP simulate conditions. However, these do not entirely replicate human condition AD. This review aims provide comprehensive evaluation historical ongoing efforts AD, particularly through use transgenic models. It focused benefits gathered from toxicity broader biological underpinnings Additionally, critically assesses application preclinical testing new therapeutic interventions, highlighting gap between clinical realities. analysis underscores need refinement methodologies bridge enhance translational value studies.

Language: Английский

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A novel Zebrafish model of Alzheimer's disease by Aluminium chloride; involving nitro-oxidative stress, neuroinflammation and cholinergic pathway

European Journal of Pharmacology, Journal Year: 2024, Volume and Issue: 965, P. 176332 - 176332

Published: Jan. 14, 2024

Language: Английский

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Microglial Responses to Alzheimer's Disease Pathology: Insights From “Omics” Studies

Glia, Journal Year: 2025, Volume and Issue: 73(3), P. 519 - 538

Published: Jan. 6, 2025

Human genetics studies lent firm evidence that microglia are key to Alzheimer's disease (AD) pathogenesis over a decade ago following the identification of AD-associated genes expressed in microglia-specific manner. However, while alterations microglial morphology and gene expression observed human postmortem brain tissue, mechanisms by which drive contribute AD pathology remain ill-defined. Numerous mouse models have been developed facilitate disambiguation biological underlying AD, incorporating amyloidosis, phosphorylated tau, or both. Over time, use multiple technologies including bulk tissue single cell transcriptomics, epigenomics, spatial proteomics, lipidomics, metabolomics shed light on heterogeneity phenotypes molecular patterns altered models. Each these 'omics provide unique information insight. Here, we review literature approaches findings methods synthesis knowledge generated applying AD.

Language: Английский

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Chaperone-Dependent Mechanisms as a Pharmacological Target for Neuroprotection

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(1), P. 823 - 823

Published: Jan. 3, 2023

Modern pharmacotherapy of neurodegenerative diseases is predominantly symptomatic and does not allow vicious circles causing disease development to break. Protein misfolding considered the most important pathogenetic factor diseases. Physiological mechanisms related function chaperones, which contribute restoration native conformation functionally proteins, evolved evolutionarily. These can be promising for pharmacological regulation. Therefore, aim this review was analyze endoplasmic reticulum stress (ER stress) unfolded protein response (UPR) in pathogenesis Data on BiP Sigma1R chaperones clinical experimental studies Alzheimer's disease, Parkinson's amyotrophic lateral sclerosis, Huntington's are presented. The possibility neuroprotective effect dependent ligand activation these also demonstrated. interaction between BiP-associated signaling neuroprotection discussed. performed analysis suggests feasibility regulation chaperone function, order achieve a effect, need further conjugation cellular controlled by chaperones.

Language: Английский

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