Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia.
Rev Neurosci. 2022 Jan 5;33(5):515-529. doi: 10.1515/revneuro-2021-0111. Print 2022 Jul 26.
Alzheimer's disease is a neurodegenerative condition that is potentially mediated by synaptic dysfunction before the onset of cognitive impairments. The disease mostly affects elderly people and there is currently no therapeutic which halts its progression. One therapeutic strategy for Alzheimer's disease is to regenerate lost synapses by targeting mechanisms involved in synaptic plasticity. This strategy has led to promising drug candidates in clinical trials, but further progress needs to be made. An unresolved problem of Alzheimer's disease is to identify the molecular mechanisms that render the aged brain susceptible to synaptic dysfunction. Understanding this susceptibility may identify drug targets which could halt, or even reverse, the disease's progression. Brain derived neurotrophic factor is a neurotrophin expressed in the brain previously implicated in Alzheimer's disease due to its involvement in synaptic plasticity. Low levels of the protein increase susceptibility to the disease and post-mortem studies consistently show reductions in its expression. A desirable therapeutic approach for Alzheimer's disease is to stimulate the expression of brain derived neurotrophic factor and potentially regenerate lost synapses. However, synthesis and secretion of the protein are regulated by complex activity-dependent mechanisms within neurons, which makes this approach challenging. Moreover, the protein is synthesised as a precursor which exerts the opposite effect of its mature form through the neurotrophin receptor p75NTR. This review will evaluate current evidence on how age-related alterations in the synthesis, processing and signalling of brain derived neurotrophic factor may increase the risk of Alzheimer's disease.
阿尔茨海默病是一种神经退行性疾病，在认知障碍出现之前，可能由突触功能障碍介导。这种疾病主要影响老年人，目前尚无阻止其进展的治疗方法。阿尔茨海默病的一种治疗策略是通过针对参与突触可塑性的机制来再生丢失的突触。这一策略在临床试验中产生了有希望的候选药物，但仍需进一步发展。阿尔茨海默病未解决的问题之一是确定使衰老大脑易患突触功能障碍的分子机制。了解这种易感性可能会确定药物靶点，从而阻止甚至逆转疾病的进展。脑源性神经营养因子是一种在大脑中表达的神经营养因子，由于其参与突触可塑性，先前被认为与阿尔茨海默病有关。该蛋白水平降低会增加患病风险，尸检研究一致表明其表达减少。刺激脑源性神经营养因子的表达并可能再生丢失的突触是治疗阿尔茨海默病的理想方法。然而，蛋白质的合成和分泌受到神经元内复杂的活动依赖性机制的调节，这使得这种方法具有挑战性。此外，该蛋白作为前体合成，通过神经生长因子受体 p75NTR 发挥与其成熟形式相反的作用。本综述将评估目前关于脑源性神经营养因子的合成、加工和信号转导与年龄相关的改变如何增加阿尔茨海默病风险的证据。
