scholarly journals The Use of Antimicrobial and Antiviral Drugs in Alzheimer’s Disease

2020 ◽  
Vol 21 (14) ◽  
pp. 4920
Author(s):  
Umar H. Iqbal ◽  
Emma Zeng ◽  
Giulio M. Pasinetti
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Potential ◽  
Amyloid Β ◽  
Physiological Role ◽  
Antiviral Drugs ◽  
Tau Proteins ◽  
The Brain ◽  
Potential Therapeutics

The aggregation and accumulation of amyloid-β plaques and tau proteins in the brain have been central characteristics in the pathophysiology of Alzheimer’s disease (AD), making them the focus of most of the research exploring potential therapeutics for this neurodegenerative disease. With success in interventions aimed at depleting amyloid-β peptides being limited at best, a greater understanding of the physiological role of amyloid-β peptides is needed. The development of amyloid-β plaques has been determined to occur 10–20 years prior to AD symptom manifestation, hence earlier interventions might be necessary to address presymptomatic AD. Furthermore, recent studies have suggested that amyloid-β peptides may play a role in innate immunity as an antimicrobial peptide. These findings, coupled with the evidence of pathogens such as viruses and bacteria in AD brains, suggests that the buildup of amyloid-β plaques could be a response to the presence of viruses and bacteria. This has led to the foundation of the antimicrobial hypothesis for AD. The present review will highlight the current understanding of amyloid-β, and the role of bacteria and viruses in AD, and will also explore the therapeutic potential of antimicrobial and antiviral drugs in Alzheimer’s disease.

Recent progress on the role of GABAergic neurotransmission in the pathogenesis of Alzheimer’s disease

2016 ◽  
Vol 27 (4) ◽  
pp. 449-455 ◽  
Author(s):  
Ghulam Abbas ◽  
Wajahat Mahmood ◽  
Nurul Kabir
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gaba Receptor ◽  
Amyloid Β ◽  
Receptor Subtypes ◽  
Causative Role ◽  
Gabaergic Neurotransmission ◽  
Promising Target ◽  
The Brain

AbstractDespite their possible causative role, targeting amyloidosis, tau phosphorylation, acetylcholine esterase, glutamate, oxidative stress and mitochondrial metabolism have not yet led to the development of drugs to cure Alzheimer’s disease (AD). Recent preclinical and clinical reports exhibit a surge in interest in the role of GABAergic neurotransmission in the pathogenesis of AD. The interaction among GABAergic signaling, amyloid-β and acetylcholine is shown to affect the homeostasis between excitation (glutamate) and inhibition (GABA) in the brain. As a consequence, over-excitation leads to neurodegeneration (excitotoxicity) and impairment in the higher level functions. Previously, the glutamate arm of this balance received the most attention. Recent literature suggests that over-excitation is primarily mediated by dysfunctional GABA signaling and can possibly be restored by rectifying anomalous metabolism observed in the GABAergic neurons during AD. Additionally, neurogenesis and synaptogenesis have also been linked with GABAergic signaling. This association may provide a basis for the needed repair mechanism. Furthermore, several preclinical interventional studies revealed that targeting various GABA receptor subtypes holds potential in overcoming the memory deficits associated with AD. In conclusion, the recent scientific literature suggests that GABAergic signaling presents itself as a promising target for anti-AD drug development.

scholarly journals Prostacyclin Promotes Degenerative Pathology in a Model of Alzheimer’s disease

2020 ◽  
Author(s):  
Tasha R. Womack ◽  
Craig Vollert ◽  
Odochi Nwoko ◽  
Monika Schmitt ◽  
Sagi Montazari ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Chronic Neuroinflammation ◽  
Model Of Alzheimer’S Disease ◽  
Amyloid Accumulation ◽  
Prostaglandin H ◽  
The Brain

AbstractAlzheimer’s disease (AD) is a progressive neurodegenerative disorder that is the most common cause of dementia in aged populations. A substantial amount of data demonstrates that chronic neuroinflammation can accelerate neurodegenerative pathologies, while epidemiological and experimental evidence suggests that the use of anti-inflammatory agents may be neuroprotective. In AD, chronic neuroinflammation results in the upregulation of cyclooxygenase and increased production of prostaglandin H2, a precursor for many vasoactive prostanoids. While it is well-established that many prostaglandins can modulate the progression of neurodegenerative disorders, the role of prostacyclin (PGI2) in the brain is poorly understood. We have conducted studies to assess the effect of elevated prostacyclin biosynthesis in a mouse model of AD. Upregulated prostacyclin expression significantly worsened multiple measures associated with amyloid disease pathologies. Mice overexpressing both amyloid and PGI2 exhibited impaired learning and memory and increased anxiety-like behavior compared with non-transgenic and PGI2 control mice. PGI2 overexpression accelerated the development of amyloid accumulation in the brain and selectively increased the production of soluble amyloid-β 42. PGI2 damaged the microvasculature through alterations in vascular length and branching; amyloid expression exacerbated these effects. Our findings demonstrate that chronic prostacyclin expression plays a novel and unexpected role that hastens the development of the AD phenotype.

scholarly journals Role of Amyloid-β and Tau Proteins in Alzheimer’s Disease: Confuting the Amyloid Cascade

2019 ◽  
Vol 68 (1) ◽  
pp. 415-415 ◽  
Author(s):  
Walter Gulisano ◽  
Daniele Maugeri ◽  
Marian A. Baltrons ◽  
Mauro Fà ◽  
Arianna Amato ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Tau Proteins ◽  
Amyloid Cascade

scholarly journals Infusion of blood from mice displaying cerebral amyloidosis accelerates amyloid pathology in animal models of Alzheimer’s disease

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Rodrigo Morales ◽  
Claudia Duran-Aniotz ◽  
Javiera Bravo-Alegria ◽  
Lisbell D. Estrada ◽  
Mohammad Shahnawaz ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Prion Diseases ◽  
Amyloid Β ◽  
Cerebral Amyloidosis ◽  
Amyloid Pathology ◽  
Tissue Extracts ◽  
The Brain ◽  
New Strategies

AbstractPrevious studies showed that injection of tissue extracts containing amyloid-β (Aβ) aggregates accelerate amyloid deposition in the brain of mouse models of Alzheimer’s disease (AD) through prion-like mechanisms. In this study, we evaluated whether brain amyloidosis could be accelerated by blood infusions, procedures that have been shown to transmit prion diseases in animals and humans. Young transgenic mice infused with whole blood or plasma from old animals with extensive Aβ deposition in their brains developed significantly higher levels brain amyloidosis and neuroinflammation compared to untreated animals or mice infused with wild type blood. Similarly, intra-venous injection of purified Aβ aggregates accelerated amyloid pathology, supporting the concept that Aβ seeds present in blood can reach the brain to promote neuropathological alterations in the brain of treated animals. However, an amyloid-enhancing effect of other factors present in the blood of donors cannot be discarded. Our results may help to understand the role of peripheral (amyloid-dependent or -independent) factors implicated in the development of AD and uncover new strategies for disease intervention.

scholarly journals Role of Amyloid-β and Tau Proteins in Alzheimer’s Disease: Confuting the Amyloid Cascade

2018 ◽  
Vol 64 (s1) ◽  
pp. S611-S631 ◽  
Author(s):  
Walter Gulisano ◽  
Daniele Maugeri ◽  
Marian A. Baltrons ◽  
Mauro Fà ◽  
Arianna Amato ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Tau Proteins ◽  
Amyloid Cascade

scholarly journals Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer’s disease

2017 ◽  
Vol 114 (45) ◽  
pp. E9645-E9654 ◽  
Author(s):  
Tatsuo Mano ◽  
Kenichi Nagata ◽  
Takashi Nonaka ◽  
Airi Tarutani ◽  
Tomohiro Imamura ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Tau Proteins ◽  
Epigenetic Mechanism ◽  
Dependent Manner ◽  
Brca1 Protein ◽  
Dna Methylome ◽  
Methylome Analysis ◽  
The Brain

Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by pathology of accumulated amyloid β (Aβ) and phosphorylated tau proteins in the brain. Postmortem degradation and cellular complexity within the brain have limited approaches to molecularly define the causal relationship between pathological features and neuronal dysfunction in AD. To overcome these limitations, we analyzed the neuron-specific DNA methylome of postmortem brain samples from AD patients, which allowed differentially hypomethylated region of the BRCA1 promoter to be identified. Expression of BRCA1 was significantly up-regulated in AD brains, consistent with its hypomethylation. BRCA1 protein levels were also elevated in response to DNA damage induced by Aβ. BRCA1 became mislocalized to the cytoplasm and highly insoluble in a tau-dependent manner, resulting in DNA fragmentation in both in vitro cellular and in vivo mouse models. BRCA1 dysfunction under Aβ burden is consistent with concomitant deterioration of genomic integrity and synaptic plasticity. The Brca1 promoter region of AD model mice brain was similarly hypomethylated, indicating an epigenetic mechanism underlying BRCA1 regulation in AD. Our results suggest deterioration of DNA integrity as a central contributing factor in AD pathogenesis. Moreover, these data demonstrate the technical feasibility of using neuron-specific DNA methylome analysis to facilitate discovery of etiological candidates in sporadic neurodegenerative diseases.

scholarly journals Involvement of Cholinergic, Adrenergic, and Glutamatergic Network Modulation with Cognitive Dysfunction in Alzheimer’s Disease

2021 ◽  
Vol 22 (5) ◽  
pp. 2283
Author(s):  
Yu-Jung Cheng ◽  
Chieh-Hsin Lin ◽  
Hsien-Yuan Lane
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Cognitive Decline ◽  
Early Stage ◽  
Amyloid Β ◽  
Tau Proteins ◽  
And Oxidative Stress

Alzheimer’s disease (AD), the most common cause of dementia, is a progressive neurodegenerative disease. The number of AD cases has been rapidly growing worldwide. Several the related etiological hypotheses include atypical amyloid β (Aβ) deposition, neurofibrillary tangles of tau proteins inside neurons, disturbed neurotransmission, inflammation, and oxidative stress. During AD progression, aberrations in neurotransmission cause cognitive decline—the main symptom of AD. Here, we review the aberrant neurotransmission systems, including cholinergic, adrenergic, and glutamatergic network, and the interactions among these systems as they pertain to AD. We also discuss the key role of N-methyl-d-aspartate receptor (NMDAR) dysfunction in AD-associated cognitive impairment. Furthermore, we summarize the results of recent studies indicating that increasing glutamatergic neurotransmission through the alteration of NMDARs shows potential for treating cognitive decline in mild cognitive impairment or early stage AD. Future studies on the long-term efficiency of NMDA-enhancing strategies in the treatment of AD are warranted.

scholarly journals Therapeutic Potential of Direct Clearance of the Amyloid-β in Alzheimer’s Disease

2020 ◽  
Vol 10 (2) ◽  
pp. 93 ◽  
Author(s):  
Dong Eun Kim ◽  
Ronny Priefer
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Potential ◽  
Advanced Glycation Endproducts ◽  
Amyloid Β ◽  
Solute Concentration ◽  
Advanced Glycation ◽  
Glycation Endproducts ◽  
The Brain ◽  
Lipoprotein Receptor Related Protein

Alzheimer’s disease (AD) is characterized by deposition and accumulation of amyloid-β (Aβ) and its corresponding plaques within the brain. Although much debate exists whether these plaques are the cause or the effect of AD, the accumulation of Aβ is linked with the imbalance between the production and clearance of Aβ. The receptor for advanced glycation endproducts (RAGE) facilitates entry of free Aβ from the peripheral stream. Conversely, lipoprotein receptor-related protein 1 (LRP1), located in the abluminal side at the blood–brain barrier mediates the efflux of Aβ. Research on altering the rates of clearance of Aβ by targeting these two pathways has been extensively study. Additionally, a cerebrospinal fluid (CSF) circulation assistant device has also been evaluated as an approach to increase solute concentration in the CSF via mechanical drainage, to allow for removal of Aβ from the brain. Herein, we provide a brief review of these approaches that are designed to re-establish a homeostatic Aβ balance in the brain.

The contribution of astrocytes to Alzheimer's disease

2014 ◽  
Vol 42 (5) ◽  
pp. 1316-1320 ◽  
Author(s):  
Amy M. Birch
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Current Evidence ◽  
Amyloid Β Peptide ◽  
Substantial Evidence ◽  
Supporting Cells ◽  
Pathological Conditions ◽  
The Brain

Astrocytes were historically classified as supporting cells; however, it is becoming increasingly clear that they actively contribute to neuronal functioning under normal and pathological conditions. As interest in the contribution of neuroinflammation to Alzheimer's disease (AD) progression has grown, manipulating glial cells has become an attractive target for future therapies. Astrocytes have largely been under-represented in studies that assess the role of glia in these processes, despite substantial evidence of astrogliosis in AD. The actual role of astrocytes in AD remains elusive, as they seem to adopt different functions dependent on disease progression and the extent of accompanying parenchymal inflammation. Astrocytes may contribute to the clearance of amyloid β-peptide (Aβ) and restrict the spread of inflammation in the brain. Conversely, they may contribute to neurodegeneration in AD by releasing neurotoxins and neglecting crucial metabolic roles. The present review summarizes current evidence on the multi-faceted functions of astrocytes in AD, highlighting the significant scope available for future therapeutic targets.

scholarly journals Tau-first subtype of Alzheimer's disease consistently identified across in vivo and post mortem studies

2020 ◽  
Author(s):  
Leon M Aksman ◽  
Neil P Oxtoby ◽  
Marzia A Scelsi ◽  
Peter A Wijeratne ◽  
Alexandra L Young ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Tau Proteins ◽  
Post Mortem ◽  
Positron Emission ◽  
Soluble Trem2 ◽  
The Brain ◽  
Insight Into

Alzheimer's disease (AD) is marked by the spread of misfolded amyloid-β and tau proteins throughout the brain. While it is commonly believed that amyloid-β abnormality drives the cascade of AD pathogenesis, several in vivo and post mortem studies indicate that in some subjects localized tau-based neurofibrillary tangles precede amyloid-β pathology. This suggests that there may be multiple distinct subtypes of protein aggregation pathways within AD, with potentially different demographic, cognitive and comorbidity profiles. We investigated this hypothesis, applying data-driven disease progression subtyping models to post mortem immunohistochemistry and in vivo positron emission tomography (PET) and cerebrospinal fluid (CSF) based measures of protein pathologies in two large observational cohorts. We consistently identified both amyloid-first and tau-first AD subtypes, where tau-first subjects had higher levels of soluble TREM2 compared to amyloid-first subjects. Our work provides insight into AD progression that may be valuable for interventional trials targeting amyloid-β and tau.

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