cAMP Compartmentalization in Cerebrovascular Endothelial Cells: New Therapeutic Opportunities in Alzheimer’s Disease

The vascular hypothesis used to explain the pathophysiology of Alzheimer’s disease (AD) suggests that a dysfunction of the cerebral microvasculature could be the beginning of alterations that ultimately leads to neuronal damage, and an abnormal increase of the blood–brain barrier (BBB) permeability plays a prominent role in this process. It is generally accepted that, in physiological conditions, cyclic AMP (cAMP) plays a key role in maintaining BBB permeability by regulating the formation of tight junctions between endothelial cells of the brain microvasculature. It is also known that intracellular cAMP signaling is highly compartmentalized into small nanodomains and localized cAMP changes are sufficient at modifying the permeability of the endothelial barrier. This spatial and temporal distribution is maintained by the enzymes involved in cAMP synthesis and degradation, by the location of its effectors, and by the existence of anchor proteins, as well as by buffers or different cytoplasm viscosities and intracellular structures limiting its diffusion. This review compiles current knowledge on the influence of cAMP compartmentalization on the endothelial barrier and, more specifically, on the BBB, laying the foundation for a new therapeutic approach in the treatment of AD.

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Molecular Genetics of Early- and Late-Onset Alzheimer’s Disease

Current Gene Therapy ◽

10.2174/1566523220666201123112822 ◽

2020 ◽

Vol 20 ◽

Author(s):

Md. Sahab Uddin ◽

Sharifa Hasana ◽

Md. Farhad Hossain ◽

Md. Siddiqul Islam ◽

Tapan Behl ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Massively Parallel Sequencing ◽

Late Onset ◽

Current Knowledge ◽

The Elderly ◽

Apoe Ε4 ◽

Sequencing Technologies ◽

Genetic Components ◽

Ε4 Allele

: Alzheimer’s disease (AD) is the most common form of dementia in the elderly and this complex disorder is associated with environmental as well as genetic components. Early-onset AD (EOAD) and late-onset AD (LOAD, more common) are major identified types of AD. The genetics of EOAD is extensively understood with three genes variants such as APP, PSEN1, and PSEN2 leading to disease. On the other hand, some common alleles including APOE are effectively associated with LOAD identified but the genetics of LOAD is not clear to date. It has been accounted that about 5% to 10% of EOAD patients can be explained through mutations in the three familiar genes of EOAD. The APOE ε4 allele augmented the severity of EOAD risk in carriers, and APOE ε4 allele was considered as a hallmark of EOAD. A great number of EOAD patients, who are not genetically explained, indicate that it is not possible to identify disease- triggering genes yet. Although several genes have been identified through using the technology of next-generation sequencing in EOAD families including SORL1, TYROBP, and NOTCH3. A number of TYROBP variants were identified through exome sequencing in EOAD patients and these TYROBP variants may increase the pathogenesis of EOAD. The existence of ε4 allele is responsible for increasing the severity of EOAD. However, several ε4 allele carriers live into their 90s that propose the presence of other LOAD genetic as well as environmental risk factors that are not identified yet. It is urgent to find out missing genetics of EOAD and LOAD etiology to discover new potential genetics facets which will assist to understand the pathological mechanism of AD. These investigations should contribute to developing a new therapeutic candidate for alleviating, reversing and preventing AD. This article based on current knowledge represents the overview of the susceptible genes of EOAD, and LOAD. Next, we represent the probable molecular mechanism which might elucidate the genetic etiology of AD and highlight the role of massively parallel sequencing technologies for novel gene discoveries.

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Alzheimer’s Disease and Retinal Degeneration: A Glimpse at Essential Trace Metals in Ocular Fluids and Tissues

Current Alzheimer Research ◽

10.2174/1567205016666191023114015 ◽

2020 ◽

Vol 16 (12) ◽

pp. 1073-1083 ◽

Cited By ~ 3

Author(s):

Alessandra Micera ◽

Luca Bruno ◽

Andrea Cacciamani ◽

Mauro Rongioletti ◽

Rosanna Squitti

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Trace Metals ◽

Late Onset ◽

Current Knowledge ◽

Pathological Condition ◽

Retinal Disease ◽

Cellular Aging ◽

Research Strategies ◽

Aged People

Background: Life expectancy is increasing all over the world, although neurodegenerative disorders might drastically affect the individual activity of aged people. Of those, Alzheimer’s Disease (AD) is one of the most social-cost age-linked diseases of industrialized countries. To date, retinal diseases seem to be more common in the developing world and characterize principally aged people. Agerelated Macular Degeneration (AMD) is a late-onset, neurodegenerative retinal disease that shares several clinical and pathological features with AD, including stress stimuli such as oxidative stress, inflammation and amyloid formations. Method: In both diseases, the detrimental intra/extra-cellular deposits have many similarities. Aging, hypercholesterolemia, hypertension, obesity, arteriosclerosis and smoking are risk factors to develop both diseases. Cellular aging routes have similar organelle and signaling patterns in retina and brain. The possibility to find out new research strategies represent a step forward to disclose potential treatment for both of them. Essential trace metals play critical roles in both physiological and pathological condition of retina, optic nerve and brain, by influencing metabolic processes chiefly upon complex multifactorial pathogenesis. Conclusion: Hence, this review addresses current knowledge about some up-to-date investigated essential trace metals associated with AD and AMD. Changes in the levels of systemic and ocular fluid essential metals might reflect the early stages of AMD, possibly disclosing neurodegeneration pathways shared with AD, which might open to potential early detection.

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Microglia in Alzheimer’s Disease

Current Alzheimer Research ◽

10.2174/1567205017666200212155234 ◽

2020 ◽

Vol 17 (1) ◽

pp. 29-43 ◽

Cited By ~ 3

Author(s):

Patrick Süß ◽

Johannes C.M. Schlachetzki

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Current Knowledge ◽

Imaging Techniques ◽

Amyloid Β ◽

Disease Stage ◽

Disease Modifying Therapy ◽

Transcriptomic Signature

: Alzheimer’s Disease (AD) is the most frequent neurodegenerative disorder. Although proteinaceous aggregates of extracellular Amyloid-β (Aβ) and intracellular hyperphosphorylated microtubule- associated tau have long been identified as characteristic neuropathological hallmarks of AD, a disease- modifying therapy against these targets has not been successful. An emerging concept is that microglia, the innate immune cells of the brain, are major players in AD pathogenesis. Microglia are longlived tissue-resident professional phagocytes that survey and rapidly respond to changes in their microenvironment. Subpopulations of microglia cluster around Aβ plaques and adopt a transcriptomic signature specifically linked to neurodegeneration. A plethora of molecules and pathways associated with microglia function and dysfunction has been identified as important players in mediating neurodegeneration. However, whether microglia exert either beneficial or detrimental effects in AD pathology may depend on the disease stage. : In this review, we summarize the current knowledge about the stage-dependent role of microglia in AD, including recent insights from genetic and gene expression profiling studies as well as novel imaging techniques focusing on microglia in human AD pathology and AD mouse models.

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In silico screening of pyridoxine carbamates for Anti-Alzheimer’s activities

Central Nervous System Agents in Medicinal Chemistry ◽

10.2174/1871524920666201119144535 ◽

2020 ◽

Vol 20 ◽

Author(s):

Dnyaneshwar Baswar ◽

Abha Sharma ◽

Awanish Mishra

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

In Silico ◽

Neurodegenerative Disorder ◽

Biological Activities ◽

Cholinergic Neurons ◽

In Silico Screening ◽

In Silico Studies ◽

Bbb Permeability ◽

Ld50 Value

Background: Alzheimer’s disease (AD), an irreversible complex neurodegenerative disorder, is most common type of dementia, with progressive loss of cholinergic neurons. Based on the multi- factorial etiology of Alzheimer’s disease, novel ligands strategy appears as up-coming approach for the development of newer molecules against AD. This study is envisaged to investigate anti-Alzheimer’s potential of 10 synthesized compounds. The screening of compounds (1-10) was carried out using in silico techniques. Methods: For in silico screening of physicochemical properties of compounds molinspiration property engine v.2018.03, Swiss ADME online web-server and pkCSM ADME were used. For pharmacodynamic prediction PASS software while toxicity profile of compounds were analyzed through ProTox-II online software. Simultaneously, molecular docking analysis was performed on mouse AChE enzyme (PDB ID:2JGE, obtained from RSCB PDB) using Auto Dock Tools 1.5.6. Results: Based on in silico studies, compound 9 and 10 have been found to have better drug likeness, LD50 value, and better anti-Alzheimer’s, nootropic activities. However, these compounds had poor blood brain barrier (BBB) permeability. Compound 4 and 9 were predicted with better docking score for AChE enzyme. Conclusion: The outcome of in silico studies have suggested, out of various substitutions at different positions of pyridoxine-carbamate, compound 9 have shown promising drug likeness, with better safety and efficacy profile for anti-Alzheimer’s activity. However, BBB permeability appears as one the major limitation of all these compounds. Further studies are required to confirm its biological activities.

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Main Plant Extracts’ Active Properties Effective on Scopolamine-Induced Memory Loss

American Journal of Alzheimer s Disease & Other Dementias® ◽

10.1177/1533317517715906 ◽

2017 ◽

Vol 32 (7) ◽

pp. 418-428 ◽

Cited By ~ 3

Author(s):

Ioana-Miruna Balmus ◽

Alin Ciobica

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Plant Extracts ◽

Current Knowledge ◽

Symptomatic Relief ◽

Memory Loss ◽

Current Treatment ◽

General Effect ◽

Function Loss ◽

Theory Research

Alzheimer’s disease leads to progressive cognitive function loss, which may impair both intellectual capacities and psychosocial aspects. Although the current knowledge points to a multifactorial character of Alzheimer’s disease, the most issued pathological hypothesis remains the cholinergic theory. The main animal model used in cholinergic theory research is the scopolamine-induced memory loss model. Although, in some cases, a temporary symptomatic relief can be obtained through targeting the cholinergic or glutamatergic neurotransmitter systems, no current treatment is able to stop or slow cognitive impairment. Many potentially successful therapies are often blocked by the blood–brain barrier since it exhibits permeability only for several classes of active molecules. However, the plant extracts’ active molecules are extremely diverse and heterogeneous regarding the biochemical structure. In this way, many active compounds constituting the recently tested plant extracts may exhibit the same general effect on acetylcholine pathway, but on different molecular ground, which can be successfully used in Alzheimer’s disease adjuvant therapy.

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Effects of Alzheimer’s Disease-Related Proteins on the Chirality of Brain Endothelial Cells

Cellular and Molecular Bioengineering ◽

10.1007/s12195-021-00669-w ◽

2021 ◽

Author(s):

Haokang Zhang ◽

Jie Fan ◽

Zhen Zhao ◽

Chunyu Wang ◽

Leo Q. Wan

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Endothelial Cells ◽

Brain Endothelial Cells ◽

Related Proteins

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Assessment of the therapeutic potential of hesperidin and proteomic resolution of diabetes-mediated neuronal fluctuations expediting Alzheimer’s disease

RSC Advances ◽

10.1039/c5ra01977j ◽

2015 ◽

Vol 5 (58) ◽

pp. 46965-46980 ◽

Cited By ~ 7

Author(s):

Sapna Khowal ◽

Malik M. A. Mustufa ◽

Naveen K. Chaudhary ◽

Samar Husain Naqvi ◽

Suhel Parvez ◽

...

Keyword(s):

Diabetes Mellitus ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Therapeutic Potential ◽

Neuronal Damage ◽

Early Stage ◽

Type Iii

Alzheimer’s disease (AD) has been proposed as type III diabetes mellitus. Prognosis and early stage diagnosis of AD is essentially required in diabetes to avoid extensive irreversible neuronal damage.

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Stabilization of dynamic microtubules by mDia1 drives Tau-dependent Aβ1–42 synaptotoxicity

The Journal of Cell Biology ◽

10.1083/jcb.201701045 ◽

2017 ◽

Vol 216 (10) ◽

pp. 3161-3178 ◽

Cited By ~ 20

Author(s):

Xiaoyi Qu ◽

Feng Ning Yuan ◽

Carlo Corona ◽

Silvia Pasini ◽

Maria Elena Pero ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Axonal Transport ◽

Dendritic Spines ◽

Posttranslational Modifications ◽

Hippocampal Neurons ◽

Neuronal Damage ◽

Driving Factors ◽

Hyperphosphorylated Tau ◽

Tau Hyperphosphorylation

Oligomeric Amyloid β1–42 (Aβ) plays a crucial synaptotoxic role in Alzheimer’s disease, and hyperphosphorylated tau facilitates Aβ toxicity. The link between Aβ and tau, however, remains controversial. In this study, we find that in hippocampal neurons, Aβ acutely induces tubulin posttranslational modifications (PTMs) and stabilizes dynamic microtubules (MTs) by reducing their catastrophe frequency. Silencing or acute inhibition of the formin mDia1 suppresses these activities and corrects the synaptotoxicity and deficits of axonal transport induced by Aβ. We explored the mechanism of rescue and found that stabilization of dynamic MTs promotes tau-dependent loss of dendritic spines and tau hyperphosphorylation. Collectively, these results uncover a novel role for mDia1 in Aβ-mediated synaptotoxicity and demonstrate that inhibition of MT dynamics and accumulation of PTMs are driving factors for the induction of tau-mediated neuronal damage.

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Lipid Peroxidation in Chronic Cerebral HypoperfusionInduced Neurodegeneration in Rats

IIUM Medical Journal Malaysia ◽

10.31436/imjm.v10i2.560 ◽

2020 ◽

Vol 10 (2) ◽

Author(s):

Anil Kumar S ◽

Saif SA ◽

Oothuman P ◽

Mustafa MIA

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Lipid Peroxidation ◽

Neurodegenerative Disorders ◽

Neuronal Damage ◽

Neuronal Cell ◽

Chronic Cerebral Hypoperfusion ◽

Cerebral Hypoperfusion ◽

Control Group ◽

Vessel Occlusion

Introduction: Reduced cerebral blood ﬂ ow is associated with neurodegenerative disorders and dementia, in particular. Experimental evidence has demonstrated the initiating role of chronic cerebral hypoperfusion in neuronal damage to the hippocampus, the cerebral cortex, the white matter areas and the visual system. Permanent, bilateral occlusion of the common carotid arteries of rats (two vessel occlusion - 2VO) has been introduced for the reproduction of chronic cerebral hypoperfusion as it occurs in Alzheimer’s disease and human aging. Increased generation of free radicals through lipid peroxidation can damage neuronal cell membrane. Markers of lipid peroxidation have been found to be elevated in brain tissues and body ﬂ uids in neurodegenerative diseases, including Alzheimer’s disease, Parkinson disease and amyotrophic lateral sclerosis. Materials and Methods: Malondialdehyde (MDA), ﬁnal product of lipid peroxidation, was estimated by thiobarbituric acid-reactive substances (TBARS) assay kit at eight weeks after induction of 2VO in the rats and control group. Results: Our study revealed a highly signiﬁ cant (p<0.001) increase in the mean MDA concentration (12.296 ± 1.113 μM) in 2VO rats as compared to the control group (5.286 ± 0.363 μM) rats. Conclusion: Therapeutic strategies to modulate lipid peroxidation early throughout the course of the disease may be promising in slowing or possibly preventing neurodegenerative disorders.

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