Studying the Progression of Amyloid Pathology and Its Therapy Using Translational Longitudinal Model of Accumulation and Distribution of Amyloid Beta
نویسندگان
چکیده
Long-term effects of amyloid targeted therapy can be studied using a mechanistic translational model of amyloid beta (Aβ) distribution and aggregation calibrated on published data in mouse and human species. Alzheimer disease (AD) pathology is modeled utilizing age-dependent pathological evolution for rate constants and several variants of explicit functions for Aβ toxicity influencing cognitive outcomes (Adas-cog). Preventive Aβ targeted therapies were simulated to minimize the Aβ difference from healthy physiological levels. Therapeutic targeted simulations provided similar predictions for mouse and human studies. Our model predicts that: (1) at least 1 year (2 years for preclinical AD) of treatment is needed to observe cognitive effects; (2) under the hypothesis with functional importance of Aβ, a 15% decrease in Aβ (using an imaging biomarker) is related to 15-20% cognition improvement by immunotherapy. Despite negative outcomes in clinical trials, Aβ continues to remain a prospective target demanding careful assessment of mechanistic effect and duration of trial design.
منابع مشابه
Involvement of TRPM7 calcium channels and PI3K/AKT kinase pathway in protective effect of vascular endothelial growth factor in amyloid beta-induced model of Alzheimer’s disease
Background and Objective: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, in which cortical and hippocampus neurons death is the main target of neurodegeneration. In addition to extracellular beta amyloid accumulation and the production of neural tangles, one of effective factors in the pathology of Alzheimer's disease is vascular injury in the elderly including disturbanc...
متن کاملVitamin E therapy prevents the accumulation of congophilic amyloid plaques and neurofibrillary tangles in the hippocampus in a rat model of Alzheimer’s disease
Objective(s): Vitamin E may have beneficial effects on oxidative stress and Aβ-associated reactive oxygen species production in Alzheimer’s disease. But, the exact role of vitamin E as a treatment for Alzheimer’s disease pathogenesis still needs to be studied. Hence, we examined the therapeutic effects of vitamin E on the density of congophilic amyloid plaques and neur...
متن کاملP135: The Role of Amyloid Beta-Peptides and Tau Protein in Alzheimer\'s Disease
Alzheimer's desease is the most common age-related neurodegenerative disorder, and cognitive problems such as defects in learning and memory are of its symptoms. Among the factors involved in the pathogenesis of the disease are biochemical disorders in protein production, oxidative stress, decreased acetylcholine secretion and inflammation of the brain tissue. Extra-neuronal accumulation ...
متن کاملThymoquinone recovers learning function in a rat model of Alzheimer’s disease
Objective: Alzheimer's disease is a neurodegenerative disorder characterized by accumulation of amyloid beta in the hippocampus. In recent decades, herbal medicine has been widely used to treat many neurodegenerative disorders,as in comparison to conventional drugs, herbal remedies exert minimal side effects. Here, the effects of thymoquinone, as the main active component of Nigella sativa, on ...
متن کاملنقش گیرندههای نیکوتینی استیل کولین، پروتئین کیناز B و پروتئین کیناز Mζ بر اثر حفاظتی اسید رزمارینیک در مدل بیماری آلزایمر القا شده به وسیلهی بتا آمیلوئید (35-25) در موش صحرایی
Background and Objective: Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases and results from the extracellular accumulation of b-amyloid peptides and the resulting neuronal dysfunction. In this study, the role of nicotinic acetylcholine receptors, protein kinase B (PKB) and protein kinase M (PKM) were evaluated in order to examine the mechanism of the protective effe...
متن کامل