Current Alzheimer Research

The increasing availability of high-dimensional omic data, such as Genome-wide Association Studies (GWAS), transcriptomic, and metabolomic data, makes it possible to identify molecular characteristics potentially associated with Alzheimer’s Disease (AD) pathology. The present contributions in this Thematic Issue reflect the efforts of the most relevant research groups in the scientific field of omics research and the challenge the use of “Big Data" in AD. Although GWAS have identified novel associations underlying susceptibility to AD, most of these genetic variants explained only modest fractions of disease heritability. Thus, it is crucial to shift from the view of single gene to a pathway perspective, in which system-wide interactions in multiple biological levels together define the disease state. Pathway- and network- driven models provide ideal vehicles for integrating relevant findings from GWAS and other modalities to enhance understanding of disease mechanism. The paper contributed by Shen and Liang et al. applied Dense Module Search algorithm, which proposed a “dual-evaluation” strategy to investigate collective effects of multiple genetic association signals for Alzheimer’s disease on an AV-45 PET measurement [1]. Their investigation of co-operating groups of genes, not only confirmed previously reported AD genes, but also highlighted several new candidate genes, their genetic functional relationship and molecular pathways underlying AD, and other types of neurodegenerative diseases. Whole transcriptome analyses may offer new insights into the pathophysiology of AD from a systems perspective [2]. By using a qualitative methodology based on within-sample relative expression orderings of genes, Hong et al. examined the gene expression patterns in four brain regions of AD and proposed that two main distinct expression patterns existed in AD. Therefore, it was concluded that that aging might be one of the reasons for the heterogeneous expression of AD [3]. Metabolomics, which measures the biochemical products of cell processes downstream of genomic, transcriptomic, and proteomic systems, has generated significant research interest because of its potential to capture early AD-related changes of metabolites. An increasing evidence has shown that the gut microbiota plays a potential role in the pathogenesis of AD, therefore, it is essential to examine alterations in metabolites of Outer Membrane Vesicles (OMVs) secreted by gut microbiota. In this issue, Liu and colleagues made an effort to provide an insight into this matter. They identified 18 specific metabolites altered remarkably in the OMVs of AD patients. The pathway and function analysis identified that several of the most commonly altered metabolic pathways are associated with AD, including the cholinergic synapse, tryptophan metabolism, phenylalanine, tyrosine, and tryptophan biosynthesis pathways [4]. The metabolic signatures identified might provide insights into further understanding of alterations in complex biological networks involved in AD. Genome-wide association studies have identified variants of the gene that encode Phosphatidylinositol Binding Clathrin Assembly Protein (PICALM) - an endocytic-related protein - as risk factors for Late-onset AD (LOAD). However, subsequent replication studies on the association between PICALM gene variants and AD have revealed inconsistent results. The paper by Zeng et al. conducted an updated meta-analysis to highlight the current evidence on the roles of three polymorphisms (rs3851179, rs541458, and rs592297) of PICALM gene in susceptibility to AD. Through a more comprehensive searching approach, their results provided evidence of a significantly decreased risk of AD for rs3851179 and rs541458 polymorphisms under all genetic models, but no association between rs592297 and AD risk [5]. SNP rs3851179 may confer reduced AD risk by increasing PICALM expression in the microvasculature [6]. The role of Cyclin-dependent kinase 5 (Cdk5) in the pathology of AD has been of great significance in the last decades. An abnormal elevation of Cdk5 activity is associated with Aβ generation, and synaptic abnormality observed in the AD brain. Recently, an integrative computational evaluation (by integrating large scale literature knowledge data, independent gene expression data and related pathway/network information) confirmed CDK5 as an AD candidate gene [7]. The review by Cai's group presented an in-depth overview of the recent findings in the role of Cdk5 in Aβ production and accumulation. The insight into how Cdk5 actively participates in AD pathology may open new avenues for a promising new class of Cdk5-directed therapeutic targets [8]. Recent GWAS studies have identified several inflammation-related AD genetic risk factors (e.g., CR1, CD33, TREM2, MS4A), implicating microglia, and the innate immune system as pivotal factors in AD pathogenesis. TREM2 (triggering receptor expressed on myeloid cells 2), an immune receptor that is exclusively expressed in the brain microglia, is thought to trigger microglial response to amyloid plaques. Most of the AD-associated TREM2 mutations are present in exons that impair TREM2 function. They may compromise microglial clearance of Aβ aggregation [9]. In this issue, Singh et al. provided a review of the current literature on how TREM2-related microglial dysregulation is associated with AD, with special attention to its impact on β-amyloid plaques and tau pathology.

Alzheimer's Disease (AD) is the most common neurodegenerative illness in the elderly. Its symptoms include progressive memory deterioration and loss of functional independence in multiple cognitive domains. Currently, AD can only be treated with acetylcholinesterase inhibitors or NMDA receptor antagonists, but these drugs only provide a symptomatic relief for a limited time. The medical, economic, and social issues associated with the worldwide increase in the number of AD patients stimulate research in this area to find its cause and disease-modifying treatment. Since expensive clinical trials, taking advantage of immunological preparations, keep failing in recent years, nervousness of the big pharma companies is apparent worldwide. However, there seems to be a well-accepted theory, that the novel treatment of such multifactorial disease should be rather a multi-targeted “hotgun” than a “magic bullet”. Therefore, the so-called Multi Target-directed Ligands (MTDL) strategy has emerged. The present mini-thematic issue presents a review and three original articles focus on the novel approaches for AD drug development, primarily, of multipotent nature. The review article by Mezeiova et al., [1] focuses on the multipotent profile of donepezil derivatives. Namely, the authors review those donepezil analogs that are capable of targeting Amyloid-beta (Aβ) cascade, thus i) the direct interaction of compounds with Aβ, ii) AChE-induced Aβ aggregation, iii) inhibition of BACE-1 enzyme, or iv) modulating biometal balance and thus impeding Aβ assembly are all pursued. The original article by Gobec´s group [2] contributes to knowledge on novel chimeric 8-hydroxyquinoline derivatives. In their extensive article, they clearly showed that such compounds are able to competitively inhibit cathepsin B, and β-secretase activity, and to serve as chelated metal ions and simultaneously weak antioxidants. Tested ligands are non-cytotoxic with predicted blood-brain barrier permeability and the most suitable candidate exerting neuroprotective effects towards Aβ toxicity, thereby reducing the activation of caspase-3/7 and diminishing the apoptosis of treated cells. Ismaili´s group [3] presents a synthesis of novel chromone-donepezil hybrids, which beside selective affinity towards butyrylcholinesterase, also show a considerable antioxidant activity. Finally, Kaniakova et al., [4] report on the biological effect of hybrid linking memantine and 6-chlorotacrine (6-Cl-THA) into a single molecule. The study shows that the hybrid surpasses the AChE inhibitory activity of the parent compound 6-Cl- THA. Furthermore, it blocks NMDA receptors by similar efficacy and the mechanism similar to memantine. Finally, 6-Cl- THA-memantine hybrid proved quantitatively better neuroprotective effect than the parent compound memantine in a model of NMDA-induced lesion of hippocampus. In short, the present issue provides a glimpse of the MTDL strategy in the treatment of AD, and the CAR issue would stimulate further research in this fruitful area. Finally, we thank the authors and reviewers for their contributions. We also gratefully acknowledge the support of the publisher (Bentham Science), and meticulous work by the journal's editorial team.

No Text Found

No Text Found

No Text Found

No Text Found

No Text Found

No Text Found

No Text Found

No Text Found

No Text Found

No Text Found