Current Alzheimer Research

Alzheimer’s disease(AD) is an insidious and progressive disorder afflicting tens of millions of patients worldwide. It is estimated that the number will increase over hundreds of millions by 2050. Currently, there is no treatment for AD and the diagnosis is based on estimates of cognitive impairment, abnormal findings in cerebrospinal fluid (CSF) (an invasive procedure), and family history and exclusion of other neurological disorders. An expensive imaging examination by positron emission tomography (PET) is at times used to help diagnosis. At present, the confirmatory diagnosis depends on postmortem assessment of extracellular deposition of senile plaque and intracellular accumulation of neurofibrillary tangles in the central nervous system upon postmortem examination. Synaptic loss is a prominent feature of early stage AD and correlates with cognitive dysfunction and memory loss. Store-operated calcium entry (SOCE) is the process by which depletion of free calcium from endoplasmic reticulum lumen causes calcium influx across the plasma membrane. Functional SOCE is critical for maintaining sustainable calcium level in neuron and signal transduction whereas attenuated SOCE disrupts neuronal spine stability and synaptic plasticity and promotes Aβ secretion [1, 2]. Accumulated studies in the past two decades indicate SOCE is inhibited in the fibroblasts, neurons, and lymphocytes from AD animal models and AD patients [3, 4]. Thus, the mechanism by which SOCE is attenuated in AD is intensively investigated. At present, several hypotheses have been proposed. First, presenilin mutation such as PS1-M146V causes failure of calcium leakage from the ER and changes the gating property of inositol triphosphate receptor or ryanodine receptor channel [5], resulting in overloading of ER calcium thereby causing less potential to induce SOCE. Second, presenilin mutation accelerates cleavage of ER sensor STIM1 [6]. Third, autophagy induced by inhibition of ubiquitinproteasome complex and ER stress degrades STIM1 or STIM2 [7, 8], leading to inhibition of SOCE. Thus, modulation of SOCE may be a potential therapeutic strategy to slow down the progression of AD. However, SOCE activation activates autophagy by inducing calcium-calcineurin, resulting in translocation of transcription factor EB into nucleus and initiating autophagy [9], and elevated autophagy may in turn inhibit SOCE by degrading STIM proteins. Until now, most studies have focused on the regulation of SOCE in neurons and implications in AD, neglecting roles of SOCE in microglia. McLarnon reports microglia obtained from sporadic AD brains display reduced SOCE relative to SOCE values from normal individuals [10]. Diminished SOCE and increased cytoplasmic calcium under basal condition occurs in fetal human microglia subject to Aβ42 treatment compared with untreated cells. Activation of SOCE by platelet activating factor (PAF) increases where application of SOCE inhibitor reduces production of iNOS, IL-1β, TNFα, and ROS. Thus, detailed dissection of SOCE regulation in microglia may shed light on SOCE-dependent microglial signaling pathways in AD brain to abnormalities in neurovascular processes in AD. In an interesting article, Popugaeva discusses the rationale to fine-tune SOCE to treat synaptic loss and maintain stability of dendritic spines [11]. Agonists of TRPC6- dependent SOCE including N-(2-chlorophenyl)-2-(4- phenylpiperazin-1-yl)acetamide and bis{2-[(2E)-4-hydroxy- 4-oxobut-2-enoyloxy]-N,N-diethylethanamine}was used to protect against amyloid toxicity in cultures and recover longterm potentiation in 5XFAD mouse model. A negative modulator of TRPC6-dependent SOCE recovers a percentage of mushroom spine in hippocampal neurons that express PS1- ΔE9. Huang et al., discuss in detail the physiological function of SOCE and molecular mechanism to activate SOCE in neurons [12]. They further review pathogenic mechanism of inhibited SOCE in AD and potential therapeutic intervention strategy. In particular, overloading of ER calcium and presenilin mutant such as M146V cleaves STIM1, leading to SOCE inhibition. Zhou and Wu briefly discuss calcium dyshomeostasis and SOCE inhibition in AD [13]. They discuss the molecular mechanism of SOCE inhibition in familial AD. In particular, they propose that autophagy degrades STIM proteins, leading to SOCE inhibition under the context of proteasome inhibition and ER stress. This distinct mechanism possibly explains synaptic loss in sporadic AD. Finally, I sincerely appreciate the contributing authors, reviewers, and the Editor-in-Chief and manager of the journal Current Alzheimer Research, for their invaluable advice and support.

In 1906, the German psychiatrist and neuropathologist Alois Alzheimer, reported, for the first time, a case of a type of senile dementia and described it as a peculiar, severe disease process of the cerebral cortex [1]. It was not until 1910 that this disease would become known as Alzheimer’s disease (AD). Today, AD is considered the most common cause of dementia, accounting for 60-80 percent of the cases [2]. It is also considered the sixth leading cause of death in the United States [2]. AD affects all aspects of memory, behavior, and thinking, and as such, interferes with daily functioning, being a major burden to the affected individuals [2]. As its prevalence keeps on increasing, reports estimate that by the year 2050, approximately 100 million individuals worldwide will meet the diagnostic criteria for AD [3]. The greatest risk factor for AD is increasing age; indeed, the majority of individuals with AD are 65 years or older, though this disease can affect younger individuals as well [2]. Other risk factors for AD include genetic factors, such as mutations in amyloid precursor protein (APP) and presenilin (PSEN) genes, mitochondrial dysfunction, immune system dysregulation, malnutrition, head injury, and exposure to infectious agents, among others [4]. Pathophysiologically, AD is a seriously debilitating disorder characterized by the progressive loss and degeneration of neurons in the brain, leading to impairments in cognitive functions, including memory and learning [5]. As AD progresses, more neurons die and more connections between networks are lost throughout the brain, resulting in increasingly severe symptoms, such as disorientation, mood, and behavioral changes [2]. This disease imposes a severe burden not only to the affected individuals but also to their caregivers in terms of psychological stress and anxiety [6]. AD also imposes a severe burden to society in terms of health care cost, accounting for over 100 billion dollars annually in the United States alone [7]. Although there are many hypotheses regarding the causes of AD, the prevailing one is the Amyloid Cascade Hypothesis formulated in the year 1992 [8]. This hypothesis posits that the main pathological event leading to neurodegeneration and cognitive dysfunction in AD is the formation and accumulation of β-amyloid (Aβ) plaques in the brain. The accumulation of Aβ in the brain subsequently leads to a series of events, including the hyperphosphorylation of the microtubule-associated protein tau and the formation of neurofibrillary tangles (NFTs), both of which exert detrimental effects to the surrounding neurons [8]. During the last few decades, we have witnessed tremendous growth in the number of studies investigating the underlying pathophysiology of AD in the hope of finding therapeutic strategies for AD. The first line of treatment for AD comprises of the cholinesterase inhibitors donepezil, rivastigmine, and galantamine [9-11], as well as the NMDA receptor antagonist memantine [12]. Although there is substantial evidence proving the efficacy of cholinesterase inhibitors in mild to moderate cases of AD, the use of these medications is not without limitations, and common side effects include nausea, vomiting, and sleep disturbance [13]. Memantine, on the other hand, is approved for moderate to severe AD and is usually better tolerated; side effects are minor and comprise of dizziness, headache, sleep disturbance, and confusion [13]. Antidepressants and antipsychotics are also recommended for AD patients who experience neuropsychiatric symptoms, such as delusion, depression, anxiety, and agitation [14]. Non-pharmacological approaches, including the use of bright light therapy, cognitive and social stimulation therapy, and physical exercise have also been considered for the treatment of AD [15-17]. However, despite significant progress in research, it is worthwhile mentioning that there is still no cure for AD. Current treatment approaches are only symptomatic in nature, being effective in improving some of the symptoms of AD or slowing down the progression of the disease [18]. A better understanding of the underlying pathophysiology of AD is, therefore, needed. In this thematic issue, we explore the role of inflammation in AD. Several lines of evidence have supported the view that inflammation may be the key neuropathological event leading to neurodegeneration in AD [19, 20]. Numerous cells and molecules, including astrocytes, microglia, cytokines, and chemokines, participate in the complex process of AD-related neuroinflammation, leading to detrimental effects on surrounding neurons, including oxidative stress and apoptosis [19, 20]. Inflammation has also been shown to induce brain arrhythmias (i.e., changes in neural network rhythmic activity), which may affect several brain functions, including information processing, memory consolidation, executive functioning, and sensory processing [21]. Accordingly, the possibility of targeting neuroinflammation for the treatment of AD has been investigated in several studies employing animal models of AD or controlled human trials [22]. For instance, micro-RNA-mediated downregulation of proinflammatory mediators, including interleukin 1-beta (IL-1β), IL-6, and tumor necrosis factor-alpha (TNF-α), in a rat model of AD was associated with a large improvement in learning and memory performance [23]. Several other reports have explored the possibility of using pharmacological agents with anti-inflammatory properties for the treatment of AD; these include studies using non-steroidal anti-inflammatory drugs (NSAIDs) [24, 25] and glucocorticoids [26, 27], among others. However, despite significant progress in research, the link between inflammation and AD is poorly understood and numerous controversies remain regarding the therapeutic potential of anti-inflammatory agents in AD [27-29]. This thematic issue aims at providing an up-to-date understanding of the contribution of inflammation in AD and a discussion of potential avenues for diagnosis and therapeutic interventions. In the review paper by Kim and Kim, the use of inflammatory biomarkers for the diagnosis of AD is discussed, with special emphasis on neuroimaging, cerebrospinal fluid, and peripheral blood biomarkers of AD [30]. On the other hand, in the original research article by Culjak and colleagues, the association between the inflammatory cytokines tumor necrosis alpha (TNF-α), interleukin 1 alpha (IL-1α), and IL-10 with AD and mild cognitive impairment is assessed [31]. Their study, which included 645 Caucasian participants with AD or mild cognitive impairment, suggested that alteration in inflammatory responses may be associated with increased risk for AD [31]. This thematic issue also addresses the association between inflammatory chemokines and AD-related pathophysiology, including Tau phosphorylation [32]. In their study, Vaz and colleagues showed that the inflammatory chemokines IL-8 and monocyte chemoattractant protein-1 (MCP-1) induce minor cytotoxicity and increased Tau phosphorylation in vitro [32]. Reduced plasma levels of IL-8 were also observed in individuals with mild to severe dementia, suggesting that this measurement may be used as a reliable biomarker for the diagnosis of AD [32]. Finally, this thematic issue discusses potential avenues for therapeutic interventions that target the inflammatory response in AD, including the use of the electromagnetic field [33] and non-steroidal anti-inflammatory drugs [34].

There are about 44 million patients with dementia worldwide which is expected to increase to 135 million by the year 2050. Alzheimer’s Disease (AD) is the number one cause of dementia, with prevalence doubling every five years between ages 50 to 80 years. Unfortunately, there are no disease modifying drugs available for AD treatment. Several factors that may contribute to the failure of advancement in new drug development on AD treatment include: 1). Most drug development target the amyloid pathology. Although amyloid pathology may contribute to the development of AD pathology partially, it is likely not the primary root cause or main mechanism for AD dementia; 2). There is no well accepted animal model for sporadic AD (SAD) which constitutes more than 95% of AD patients, so drugs that work well in familiar AD (FAD) animal models may not be effective in patients with SAD: 3). There may be multiple pathways or mechanisms of neurodegeneration, synapse and cognitive dysfunction in AD patients, so a single drug targeting one pathological pathway may not be fully effective. A combination of drugs targeting different pathways may provide effective therapeutic effects. Among alternative approaches to study mechanisms of AD pathology and dementia, disruption of intracellular Ca2+ homeostasis has been increasingly recognized as a major upper stream pathological mechanism of AD, with many recent studies demonstrating the efficacy of old or new drugs and compounds targeting correction of Ca2+ dysregulation for AD treatment [1-3]. This thematic issue aims to illustrate the mechanisms and features of Ca2+ dysregulation in each major intracellular Ca2+ store in AD. Various Food and Drug Administration (FDA) approved clinically available drugs and novel compounds targeting different sites of pathological Ca2+ dysregulation were developed as potential new treatments of AD. Chami and Checler have discussed in detail the molecular structure, function and Regulation of Ryanodine Receptor (RyR) Ca2+ channel located on the ER membrane and its contribution to ER Ca2+ homeostasis and cell function [4]. The leaky type 2 RyR (RyR-2) mediated Ca2+ dysregulation results in worsened amyloid pathology, mitochondria dysfunction, synapse, and cognitive dysfunction. Pathological activation of Protein Kinase A (PKA) associated with β2 adrenergic signaling and the subsequent phosphorylation of RyR-2, as well the oxidation and nitrosylation of RyR-2 via different mechanisms, contribute to the excessive RyR-2 activation and associated AD pathology, which can be inhibited by the compounds that stabilize RyR-2 and minimize the pathological Ca2+ leak. Abou et al., summarized the studies demonstrating therapeutic effects of RyR, antagonist dantrolene, a clinically available drug to treat malignant hyperthermia or muscle spasms, on amelioration of Ca2+ dysregulation and associated AD pathologies, synapse and cognitive dysfunction in various cell and animal models [1, 5]. Wang et al. also proposed a novel approach to administer dantrolene intranasally in order to increase brain concentration and duration [6], which has been demonstrated to be more effective than the subcutaneous approach in ameliorating memory loss in 5xFAD mice, even as a disease modifying drug, with tolerable side effect after about 8 months treatment [7]. Nasal administration of dantrolene may further decrease the overall minimal effective therapeutic dose for treatment of AD or other neurodegenerative diseases such as stroke, spinal ischemia, seizure, Huntington’s disease and spinocerebellar ataxia etc. [8], with reduced side effects of dantrolene after chronic use. Wu et al., discussed the physiological regulation of mitochondrial Ca2+ homeostasis, especially its close relationship with the ER and the mechanisms of pathological mitochondrial Ca2+ overload, as important AD pathology and etiology. Potential targets to correct mitochondrial Ca2+ dysregulation and particular compounds were proposed and discussed [9]. Popugaeva et al., summarized the overall Ca2+ dysregulation in both familiar and sporadic AD and its essential role in many proposed AD pathology, as the potential targets and compounds for treatment of AD [10]. In particular, they explained the important role of Store Operated Ca2+ Entry (SOCE) in maintaining physiological ER Ca2+ homeostasis. Both impairment and excessive function of SOCE have been demonstrated in AD, depending on the AD mutation sites of presenilin 1 [10]. In short, this thematic issue summarized previous studies using clinically available drugs or new compounds ameliorating pathological Ca2+ dysregulation as new treatments of AD. We have proposed new approaches for future drug development based on the Ca2+ dysregulation mechanisms in AD. We thank all authors, reviewers, journal’s editorial team and publisher (Bentham Science).

Over a century after its first characterization, Alzheimer’s Disease (AD) still presents a serious diagnostic and therapeutic challenge. How pathology of AD connects to symptomology is incompletely explained. Currently, the pathogenic mechanisms of AD are explained primarily on the basis of several molecular pathways, including oxidative stress, immune response and the presence of specific genetic variants. Moreover, treatment of the patients with AD poses a vast challenge. There are no effective drugs to provide long term relief of clinical symptoms of patients with this disease or to prevent its occurrence. The present “Thematic Issue” issue in “Current Alzheimer Research” highlights the pathogenesis of AD, both in the neuroanatomical and symptomatic sense, including environmental, biochemical, and genetic factors in the clinical manifestation of this neurological disease. We also point out to the need for new treatment methods focused on the pathology of AD.

Underlying causes of clinical manifestations of AD are complex, multifactorial and poorly understood. AD is the most common cause of cognitive impairment and behavioral changes leading to dementia. Alzheimer’s dementia is associated with memory impairment, mainly current memory called “fresh memory” [1, 2]. It is not known why patients suffering from AD fail to create new memories, although their memories of old events remain mostly unaffected. Studies on the hippocampus of transgenic AD model showed that impairment of memory formation correlates with changes in glutamatergic synaptic transmission as well as neuronal plasticity disorders [3]. Furthermore, memoryrelated impairments associated with early AD are connected to synaptic plasticity disorders in the cortical-hippocampal circuits, which are also implicated in early disease progression [4, 5]. Such preclinical stage of AD has become an active area of recent basic and clinical research.

In this issue, we also report research on the causes of cognitive disorders in patients with AD. According to the currently accepted major hypothesis, AD arises mainly due to the accumulation of extraneuronal plaques primarily comprised of β-amyloid (Aβ) peptides, with important roles played by intracellular neurofibrillary tangles of excessivelyphosphorylated tau protein. Such pathological aggregates may lead to lesions first in the limbic system, hippocampus, entorhinal cortex, and Meynert’s basal ganglia, followed by the neocortex and the other basal ganglia. Moreover, central deposition of aggregated proteins may lead to excitotoxicity associated with excessive stimulation of glutamate Nmethyl- D-aspartate (NMDA) receptors and neuronal damage and death [6-8]. It should be emphasized that numerous clinical trials focused on the mechanism based on the “Amyloid Hypothesis” of AD have failed. Although it has been previously suggested that neuronal death in AD occurs by apoptosis or autophagy, more recent reports have implicated neural Programmed Cell Death (PPCD) [8]. Recent failures in AD provide an opportunity in continuing to investigate diverse approaches [9].

The thematic issue also reports other molecular factors possibly important for the pathogenesis of Alzheimer’s dementia among others: changes in the levels of biomarkers, such as acetylcholine (ACh), homocysteine (Hcy), generation of free radicals (ROS), accumulation of nuclear (nDNA) and mitochondrial (mtDNA) DNA damages, genetic variants and epigenetic modifications [10]. We also recognize other impaired functioning of the cholinergic system, including choline acetyltransferase (ChAT), acetylcholinesterase (AChE), high-affinity choline uptake (HACU), muscarinic (mAChR), and nicotinic (nAChR) cholinergic receptors [11]. Current research in the cholinergic system mainly concerns its role in modulating cognitive functions and improving its activity through selective targeting of mAChR and nAChR. AD also associates with severe loss of cholinergic system activity in the brain due to the potentially toxic interaction of tau protein with mAChR [12]. Extracellular tau may bind to mAChR, e.g., M1 and M3, and may lead to an increase in intracellular Ca2+ concentration in neuronal cells. The tau interaction with mAChR may also lead to neuronal cell death. Moreover, cholinesterase degradation is accelerated by high levels of Hcy, hyperhomocysteinemia (HHcy).

HHcy may be an independent risk factor for both AD and vascular dementia. Normal Hcy concentrations in cerebrospinal fluid (CSF) slow down Aβ aggregation, while high concentrations accelerate its aggregation [13]. HHcy may also lead to cognitive impairment by various mechanisms, such as disrupted nucleic acid (DNA, RNA) synthesis and DNA repair disorders, as well as increased sensitivity of neurons to its toxic effects [14]. Hcy may self-oxidize and increase ROS production, and additionally may lead to DNA or protein methylation disorder, and thus affect gene expression and enzyme activity. Moreover, there are several genes mentioned associated with ROS generation in AD, including: TOMM40, APOE, LPR, MAPT, APP, PSEN1 and PSEN2 [15-17].

Another feature of AD includes mitochondrial disorders such as increased mitophagy and mitochondrial dysfunction, which may lead to oxidative stress generation; however, the mechanisms that initiate these disorders are unclear [16]. Both mitochondrial dysfunction and genetic variants in the TOMM40 and APOE genes may lead to DNA damage. On the other hand, lowering the level of antioxidants (e.g. Glutathione, GSH) as well as weakening the DNA repair systems, especially in mitochondria, may lead to the development of dementia [10, 16].

Thus, the pathogenesis of AD is a complex phenomenon with both genetic and environmental components that remain poorly defined. Recently emerging evidence suggests there is also a bidirectional interaction between the intestinal microbiota and the brain [18], and perhaps a role of infectious agents of viral origin in AD; however, these hypotheses require clarification.

The thematic issue also examines therapeutic strategies in AD, including pharmacotherapy of cognitive impairment and behavioral changes as well as other symptoms. Currently used drugs increase cholinergic transmission or act as a partial NMDA receptor antagonist (memantine) [19-21]. Memantine exhibits neuroprotective effects by protecting neurons against excessive glutamatergic stimulation, reduces the “noise” of signals in the synapses and improves the Long Term Potentiation (LTP) process, responsible for learning. The cholinergic drugs include Cholinesterase Inhibitors (ChEIs) such as donepezil, rivastigmine and galantamine that increase ACh levels by various mechanisms. Donepezil selectively acts on AChE synthesized in neurons, rivastigmine acts through AChE and Butyrylcholinesterase (BuChE) synthesized in glial cells. Galantamine, in addition to its AChE activity, has a modulating effect on nAChR. Unfortunately, although procognitive cholinergic therapy may lead to an increase of ACh level in the brain of AD patients, its therapeutic effects are unclear. A fresh look at cholinergic therapy [22] suggests that Abietane diterpenoids, such as abietic acid, carnosic acid, and ferruginol, are promising natural derivatives for the treatment of some neurodegenerative diseases due to their inhibitory action on both the AChE and BuChE. It is also important to investigate experimental therapies directed against pathological proteins, including the tau protein. Notably, the tau aggregation inhibitor leuco-methylthioninium bis (hydromethanesulfonate), LMTM may increase ACh levels in the hippocampus and reduce spatial learning deficits based on the studies conducted in transgenic tau expressing mice. This gives hope for the improvement of clinical symptoms in tauopathies [23].

Regarding genetic factors, research is being carried out on the impact of gene variants such as ABCB1, ACE, CHAT, CHRNA7, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, CYP3A7, NR1I2, NR1I3, POR, PPAR, RXR, SLC22LC1/2/5, UGT, UGT1A9 and UGT2B7 and on the efficacy of pharmacotherapy in AD. Genetic variants of these genes may modulate ACh formation and metabolism as well as transport, metabolism and excretion of drugs modulating neurotransmitter’s level. The most promising results were demonstrated for APOE e4, the best known genetic risk factor for dementia, BCHE-K, a reduced BuChE activity variant and CYP2D6, a UM variant that leads to ultrafast hepatic metabolism [24]. Furthermore, genetic factors play an important role in inter-individual variability in drug response [25]. Besides, epigenetic factors are also important. Environmental factors, including early-life exposure, education, exercise, and diet, play a crucial part in this human disease, particularly as heterogeneous as AD [26].

Despite current available FDA-approved drugs for AD, effective long-term pharmacotherapy of AD is currently unknown. Hence the search and definition of effective treatment of potential, modifiable risk factors, including molecular ones, are becoming all the more important. Treatment, nevertheless, may be possible based on monoclonal antibodies that give increasing hope for the introduction of biological treatment of AD in the near future [27].

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.

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