Progress in Biochemistry and Biophysics -->Special Topic: Alzheimer's Research

Editorial

HE Rong-Qiao — 2021/8/24 0:00:00

《2021 年阿尔茨海默病事实和数据》（Alzheimer’s Association）强调了阿尔茨海默病（Alzheimer’s disease，AD）是最常见的痴呆症. 伴随人类老龄化的日益严重，AD已被列为美国的第六大死因，在我国已成为第五大死因，且死亡率呈逐年上升趋势. 《2019 年世界阿尔茨海默病报告：对痴呆症的态度》估计全球有超过5 000 万人患有痴呆症，预计到2050 年，这个数字可能增加到1.52 亿［1］ . 面对AD对老年人健康日益加重的危害，各国投入了大量的人力、财力、物力以推动不同学科，从不同角度开展对AD的基础和临床研究. 其研究热点出现了一系列的变化趋势，如重视突触可塑性与认知能力、脑的能量代谢与线粒体的结构、溶酶体与脑内蛋白质稳态等研究，包括神经元损伤与修复、自噬与神经元变性死亡、神经元与神经胶质细胞的协调、外泌体的结构与功能、慢性炎症等. 另一方面，大数据与影像、临床、组学等多模数据结合与分析，在AD的病理、诊断、干预和治疗方面的应用，促进了我们对AD的认识和理解.
本期《生物化学与生物物理进展》刊出了4 篇论文，从不同的角度探讨和研究了有关AD的发病机制和潜在的治疗方法. 过氧化物酶体增殖物激活受体（peroxisome proliferators-activated receptor，PPAR）属于核受体，在中枢神经系统中表达，具有调节能量代谢、神经传递、氧化还原稳态、线粒体等功能. 吕明媞等［2］综述了过氧化物酶体增殖物激活受体的一个亚型，PPARα，在控制突触可塑性和调节认知功能中的重要作用及其与AD的关系.高君妍等［3］介绍了诱导神经再生的方法及其在治疗AD的作用机制，展望了通过诱导神经再生，从而有效地改善AD的症状的前景. 金宇等［4］探讨了基于遗传数据的机器学习在AD研究中的应用，其主要内容包括：遗传数据与影像、临床、组学等多模数据结合的AD诊断和预后等. 通过AD患者数据库、脑片观察、小鼠模型的分析，路亚岚等［5］发现细胞凋亡抑制家族蛋白Survivin，可能通过NF-κB-Survivin 轴抑制细胞的凋亡，从而有望在延缓AD病理进程中发挥一定的作用. 上述4 篇论文选题和内容属于当前AD研究的前沿，基于作者的专业视野或研究结果为相关领域的研究提供了新的思路和线索. 在此集成《阿尔茨海默病研究专题》，以飨读者.

PPARα in Alzheimer’s Disease

Lü Ming-Ti,YANG Zhi-Jun and ZHANG Wei — 2021/8/24 0:00:00

Alzheimer’s disease (AD) is a neurodegenerative disease with progressive and persistent cognition and memory destruction. Its main pathological features are β-amyloid (Aβ) deposition and neurofibril tangles formed by hyperphosphorylated Tau protein, which is becoming a serious global health problem. Peroxisome proliferators-activated receptors (PPARs) is a nuclear receptor that expresses in the central nervous system and regulates energy metabolism, neurotransmission, redox homeostasis, mitochondrial function and other physiological processes. PPARα, as one of the subtypes, plays an important role in the control of synaptic plasticity and neuronal function. In this review, we discussed the possibility of PPARα as a therapeutic target for AD treatment. PPARα can reduce the production of soluble amyloid precursor protein (sAPP) and Aβ by regulating β secretase-1 (BACE-1) and reduce the accumulation of reactive oxygen species (ROS) by regulating the function of mitochondria, thereby decreasing oxidative stress damage. PPARα can down-regulate inflammatory factors and lessen neuroinflammation. It can also decrease blood lipids, alleviate insulin resistance, and regulate lipids metabolism. PPARα, as a promising target for the treatment of AD, is of great significance to new treatment strategies for AD.

Research Progress on The Mechanisms of Inducing Nerve Regeneration in The Treatment of Alzheimerʼs Disease

2021/8/24 0:00:00

Alzheimer?s disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment and memory loss in the central nervous system, which has become one of the most difficult problems and urgent to solve in geriatrics. However, the pathological mechanism of AD is still unclear, and there is no specific medicine for AD. Currently, the exploration of nerve regeneration in AD has gradually attracted increasing attention. Increasing BDNF or NGF expression by neurotrophic solution or adeno-associated virus can regulate the survival of nerve cells and the plasticity of synapses. AChEI drugs can inhibit the decomposition of ACh and activate the nAChRs receptor, which enhance growth, communication and survival of neurons. Brain stimulation techniques such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) can activate synaptic activity in neuronal circuits. Exogenous NSCs transplantation or BDNF combined with NSCs transplantation can not only directly increase the number of neurons, but also indirectly improve pathology surroundings by stimulating the secretion of neurotrophic factors and exosomes. Studies have demonstrated that the treatment of neurotrophic solution, physical stimulation or stem cell transplantation can enhance adult neurogenesis in the brain, which is considered to be effective strategy to alleviate pathological symptoms as well as cognitive impairment of AD. However, the optimal intervention strategy and the quality of treatment need to be further evaluated. Our paper reviews the methods of inducing nerve regeneration and elucidates its therapeutic mechanism of AD, which may provide a theoretical basis for the implementation of nerve regeneration therapy.

Application of Machine Learning Based on Genetic Data in The Study of Alzheimer’s Disease

JIN Yu,YAO Xu-Feng,HAN Li-Ting,ZHAO Cong-Yi and HUANG Gang — 2021/8/24 0:00:00

Alzheimer’s disease (AD), a neurodegenerative disease, is closely related to the genetic and environmental factors, about 70% of which are caused by the genetic factors, but its pathogenesis is still unclear. Along with the advent of high-throughput gene sequencing, the processing of genetic data using machine learning (ML) has become a hot spot. In this paper, the applications of ML in AD are mainly reviewed, including the diagnosis and prognosis of AD based on genetic data, the analysis of genetic variation of AD, the analysis of gene expression profile of AD, and the further development of ML for AD. Firstly, during the diagnosis and prognosis of AD, the genetic data combining with other modalities, such as imaging data, clinical data and histological data, would be greatly improved the accuracy of ML methods. It is valuable for the early diagnosis of AD, and effectively delays the progression of AD. Secondly, the application of ML in the analysis of genetic variation of AD, single nucleotide polymorphisms (SNPs) of new genes were dug out, and the pathogenic mechanism of AD was further explored. Thirdly, the analysis of gene expression profile of AD mainly focuses on the discovery of the pathways of genes which could provide the possibility of gene targets for AD therapy. In the future, the multi-level model of ML might be developed for high-quality, diverse and large data, and provide scientific strategies for exploring the pathogenesis of AD.

The Expression and Preliminary Mechanism of IAPs Family Proteins in Alzheimer’s Disease’s Animal Models

LU Ya-Lan,ZHOU Li,HAN Yun-Lin,WANG Ke-Wei and QIN Chuan — 2021/8/24 0:00:00

As the increasing aging population globally, Alzheimer’s disease (AD) has been the most common type of neurodegenerative disease, characterized with progressive cognitive impairment. The main pathological features were senile plaques, neurofibrillary tangles and neurons and synapse loss. Inhibitor of apoptosis family proteins (IAPs) are a class of endogenous apoptosis inhibitors, and their function in the pathological process of AD has not been clear. In this study, IAPs protein expression were analyzed from AD patient databases, AD animal models and brain slice models. NFκB signaling pathway was detected by EMSA and immunoblotting. The results show that Survivin acts as a co-upregulated gene in all models including AD patients, AD mouse models and Aβ, okadaic acid and LPS induced brain slices. NFκB signaling pathway was significantly activated, and they exhibited the similar expression profile. Therefore, the cell apoptosis in AD progression may be inhibited by NFκB/IAPs axis. Survivin may be an important target for AD prevention and treatment.

Review: Research Progress of Epigenetic Modification in The Regulation of Alzheimer’s Disease

2022/4/22 0:00:00

Alzheimer’s disease (AD) is a clinically common neurodegenerative disease characterized by progressive cognitive dysfunction and memory loss. In recent years, studies have found that various epigenetic modifications such as DNA modification, histone modification, RNA modification and non-coding RNA play pivotal roles in the regulation of Aβ deposition, hyperphosphorylated Tau proteins, nerve regeneration, synaptic plasticity and cognitive function, thereby improving or aggravating the pathological process of AD. Decreasing 5-methylcytosine of PSEN1 and BACE1 genes may cause Aβ production via promotion of PSEN1 and BACE1 expression. Increasing DNA modifications of 5-hydroxymethylcytosine by Tet1/Tet2/Tet3 protein can regulate proliferation, differentiation and function of neurons, neural stem cells, and neural progenitor cells. Moreover, increasing histone methylation (H3K9me2 and H3K4me3) and demethylation (H3K27me3) catalyzed by histone methyltransferase and demethylase respectively can decrease neuronal differentiation and cognition. Low acetylation levels of histones maintained by the suppression of histone acetylases and activation of histone deacetylases (HDAC2, HDAC3 and HDAC6) can be contributed to inducing cognitive impairment. Furthermore, N⁶-methyladenosine (m6A) RNA modification catalyzed by the RNA methyltransferases Mettl3 and Mettl14 (writers), removed by the demethylases FTO (erasers), and interacted with m6A-binding proteins YTHDF1 and YTHDF (readers) is involved in synaptic plasticity, neuronal apoptosis and synaptic transmission. In addition, low expression of miR-29, miR-31 and miR-101 causes Aβ deposition by improving BACE1 and APP levels. Either declining miR-34a, miR-219 or raising miR-128a, miR-125b, and miR-124 can lead to high levels of Tau protein and Tau hyperphosphorylation. The up-regulation of miR-137 and miR-142 can reduce synaptic plasticity and stimulate neuroinflammation, respectively. Overexpression of lncRNA BACE1-AS and BC200 can promote Aβ deposition by boosting BACE1 expression, while enhancing BDNF-AS and GDNFOS result in neurodevelopment disorder by inhibiting BDNF and GDNF expression. Clinical data shows that changes in epigenetic modifications are significantly correlated with AD risk. The use of drugs, physical stimulation, siRNA and other interventions to change the level of epigenetic modifications in AD animal models can ameliorate AD pathology and cognitive impairment. Our paper reviews the regulatory effects of various epigenetic modifications in AD and in the hope of providing a theoretical basis for further understanding of the epigenetic mechanism in AD and a feasible interventions for preventing or treating AD via alteration epigenetic modifications.

Review: ABCA7 and Alzheimer’s Disease Pathogenesis

2022/4/22 0:00:00

Alzheimer’s disease (AD), a serious degenerative disease of the central nervous system, is the most common cause of dementia in the elderly. Its etiology has not yet been elucidated. ATP-binding cassette transporter A7 (ABCA7) has a high level expression in the brain. Since the genome-wide association studies identified ABCA7 as a risk gene for AD, more and more evidence from in vitro, in vivo, and human-based studies has confirmed that ABCA7 is one of the most important risk genes for early-onset and late-onset AD. ABCA7 mediates phospholipid efflux and its distribution in neurons, and plays a weak but significant role in cholesterol regulation, so as to maintain the lipid homeostasis in the brain. ABCA7 is also closely related to microglia phagocytosis and immune function. When lipid homeostasis in the brain is unbalanced or ABCA7 is defective, it will reduce the ability of microglia to process Aβ, causing abnormal accumulation of Aβ and triggering the inflammatory response in the brain. ABCA7 single nucleotide polymorphism (SNP) variants or loss-of-function (LOF) mutations are also significantly associated to the risk of AD. We suggest that ABCA7 may be a potential biomarker or therapeutic target for early detection and diagnosis of AD. In this paper, the role of ABCA7 in the occurrence and development of AD is reviewed, in order to provide therapeutic ideas for the clinical prevention and treatment of AD.

Research: Screening of Key E3 Ubiquitin Ligase in The Development of Alzheimer’s Disease

LU Ya-Lan,SHI Gui-Ying,WANG Ke-Wei and BAI Lin — 2022/4/22 0:00:00

Objective To explore the key E3 ubiquitin ligases and their expression profile in the pathogenesis of Alzheimer’s disease (AD).Methods Bioinformatics method was used to screen the differential expression genes (DEGs) in the development of AD. The DEGs were analyzed by gene ontology (GO) and protein-protein interaction (PPI) network. Then, the E3 ubiquitin ligases were looked up through The Human Protein Atlas and Alzdata databases to find their histocytological localization in different brain regions. It was verified by qPCR in AD mice brain tissue.Results Ubiquitin-proteasome system (UPS) and ubiquitin conjugating enzyme from Trypanosoma cruzi (UBCc) domains of ubiquitin-conjugating enzyme were ranked top in the biological functions and domains involved in the process of AD; PPI network revealed multiple UPS molecules are the key node proteins; brain tissues specific and highly expressed E3 ubiquitin ligases (MKRN2, NEDD4L, LNX1, RNF41, TRIM36, RNF8 and DTX4) are reduced in AD patients and AD mice.Conclusion These 7 E3 ubiquitin ligases may function as driving factors to participate in the progress of AD, which provides important clues for further searching for new targets for the diagnosis, treatment and in-depth mechanism exploration in AD progression.

Research: Anxiety is a Risk Factor of AD at an Early Stage With Gender Differences in APP V717I Transgenic Mice

2022/4/22 0:00:00

Objective Alzheimer’s disease (AD) is the most common form of dementia. There are two main risk factors for developing AD—age and gender. By aging, preclinical and clinical symptoms are emerging in succession. Anxiety is one of the typical early symptoms during AD processing. Besides, the incidence of AD is higher in women than in men. However, although the differences were observed in the AD cohort, there is a lack of the assessment of AD experimental animal models within age and gender.Methods We choose the APP London mutation (Val717Ile) transgenic (Tg) mice for study. This is one of the first described mutations in APP, with the early onset of AD. To illustrate if the gender difference occurred in APP V717I mice during AD processing, we made use of animal behavior tests, such as open field test, step-down test and Morris water maze to evaluate the non-cognitive symptom and cognitive symptom.Results In this study, we found that at 6-month age, female Tg mice showed significant anxiety, while male Tg mice only showed anxiety at 10-month age. At 6-month age, both male and female Tg mice did not show cognitive deficits; but, at 10-month age, both genders showed significant cognitive impairments.Conclusion These results indicated that APP V717I Tg mice showed anxiety-like activity before the occurrence of memory deficits; in the process of AD, APP V717I Tg mice have a clear difference in age and gender. This study provides favorable evidence for age and gender differences in the process of AD. The mouse model is also expected to become an essential tool for AD drug research, aiming to help precision medicine and distinguish gender differences in drug use.

Research: Elevated DISC1 Promoter Methylation Increases The Risk of Alzheimer’s Disease

2022/4/22 0:00:00

Objective Aberrant promoter methylation of multiple genes is associated with various diseases, including Alzheimer’s disease (AD), however, the relationship between disrupted-in-schizophrenia-1 (DISC1) promoter methylation and the progress of AD is unclear.Methods The methylation levels of the DISC1 promoter were measured in 51 AD patients and 63 controls using bisulfite pyrosequencing assay. Blood biochemical indicators were detected using standard methods.Results DISC1 promoter methylation was significantly higher in AD patients than in controls (P=0.002). Moreover, Both apolipoprotein A (ApoA) and Lipoprotein A (Lp(a)) are significantly correlated with the DISC1 CpG3 methylation. DISC1 methylation is positively correlated with blood ApoA in female (P=0.003). DISC1 methylation is positively correlated with blood Lp(a) in male (P<0.000 1). The area under curve (AUC) of DISC1 promoter methylation is 0.726 (95% CI: 0.626-0.827), the sensitivity is 0.560 and specificity is 0.869.Conclusion The results of the present study demonstrated that elevated DISC1 promoter methylation was associated with AD risk in males, and it may be a potential biomarker for the diagnosis of AD.