ISSN (Print): 1567-2050
ISSN (Online): 1875-5828
Volume 17, 14 Issues, 2020
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ISSN (Print): 1567-2050
ISSN (Online): 1875-5828
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Special Issue Submission
"Current Alzheimer Research is a great source of the most relevant and timely research in the field of AD research."
Rudolph E. Tanzi
Massachusetts General Hospital, and Harvard Medical School, USA
My experience with Bentham Science Publishers’ "Current Alzheimer Research" was positive. While the review process of the manuscript was a bit too long, on the other hand the great contribution given by the Editor in Chief to the interpretation of the data I presented was brilliant. His suggestions have greatly improved the quality of my manuscript and so at the end my experience was very positive.
Rosanna Squitt (Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio- Fatebenefratelli, Brescia, Italy.)
1 Articles Ahead of Print are available electronically
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
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 .
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 ,
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 . 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. , with reduced side effects of dantrolene after
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 .
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 . 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 .
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.
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 . 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 . 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 .
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 . 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 . SNP rs3851179 may confer reduced AD risk
by increasing PICALM expression in the microvasculature .
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 . 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
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 . 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
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.,  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  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  presents a synthesis of novel chromone-donepezil hybrids, which beside selective affinity towards butyrylcholinesterase,
also show a considerable antioxidant activity.
Finally, Kaniakova et al.,  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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