scholarly journals Searching for an endogenous anti-Alzheimer molecule: identifying small molecules in the brain that slow Alzheimer disease progression by inhibition of β-amyloid aggregation

2013 ◽  
Vol 38 (4) ◽  
pp. 269-275 ◽  
Author(s):  
Autumn Meek ◽  
Gordon Simms ◽  
Donald Weaver
Keyword(s):  
Alzheimer Disease ◽  
Small Molecules ◽  
Disease Progression ◽  
Amyloid Aggregation ◽  
Β Amyloid ◽  
The Brain

Oriental medicine Jangwonhwan reduces Aβ(1–42) level and β-amyloid deposition in the brain of Tg-APPswe/PS1dE9 mouse model of Alzheimer disease

2010 ◽  
Vol 128 (1) ◽  
pp. 206-212 ◽  
Author(s):  
Ji-Seon Seo ◽  
Jong-Hyun Yun ◽  
In-Sun Baek ◽  
Yeo-Hyun Leem ◽  
Hyung-Won Kang ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Mouse Model ◽  
Amyloid Deposition ◽  
Oriental Medicine ◽  
Β Amyloid ◽  
The Brain

scholarly journals Can Anti–β-amyloid Monoclonal Antibodies Work in Autosomal Dominant Alzheimer Disease?

2020 ◽  
Vol 7 (1) ◽  
pp. e535
Author(s):  
Bruno P. Imbimbo ◽  
Ugo Lucca ◽  
Mark Watling
Keyword(s):  
Alzheimer Disease ◽  
Cognitive Decline ◽  
Autosomal Dominant ◽  
Amyloid Β ◽  
Functional Deficits ◽  
Β Amyloid ◽  
Set Up ◽  
The Brain ◽  
Dominant Theory

The dominant theory of Alzheimer disease (AD) has been that amyloid-β (Aβ) accumulation in the brain is the initial cause of the degeneration leading to cognitive and functional deficits. Autosomal dominant Alzheimer disease (ADAD), in which pathologic mutations of the amyloid precursor protein (APP) or presenilins (PSENs) genes are known to cause abnormalities of Aβ metabolism, should thus offer perhaps the best opportunity to test anti-Aβ drugs. Two long-term preventive studies (Dominantly Inherited Alzheimer Network Trials Unit Adaptive Prevention Trial [DIAN-TU-APT] and Alzheimer Preventive Initiative–ADAD) were set up to evaluate the efficacy of monoclonal anti-Aβ antibodies (solanezumab, gantenerumab, and crenezumab) in carriers of ADAD, but the results of the DIAN-TU-APT study have shown that neither solanezumab nor gantenerumab slowed cognitive decline in 144 subjects with ADAD followed for 4 years, despite one of the drugs (gantenerumab) significantly affected biomarkers relevant to their intended mechanism of action. Surprisingly, solanezumab significantly accelerated cognitive decline of both asymptomatic and symptomatic subjects. These failures further undermine the Aβ hypothesis and could support the suggestion that ADAD is triggered by accumulation of other APP metabolites, rather than Aβ.

scholarly journals Absence of Alzheimer Disease Neuropathologic Changes in Eyes of Subjects With Alzheimer Disease

2017 ◽  
Vol 76 (5) ◽  
pp. 376-383 ◽  
Author(s):  
Erik A. Williams ◽  
Declan McGuone ◽  
Matthew P. Frosch ◽  
Bradley T. Hyman ◽  
Nora Laver ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Macular Degeneration ◽  
The Elderly ◽  
Protein Accumulation ◽  
Intracellular Accumulation ◽  
Visual Deficits ◽  
Hyperphosphorylated Tau Protein ◽  
Pathologic Findings ◽  
Β Amyloid ◽  
The Brain

Alzheimer disease (AD) is the most common cause of dementia in the elderly, and is characterized by extracellular deposition of β-amyloid and intracellular accumulation of hyperphosphorylated tau protein in the brain. These pathologic findings are identified postmortem. Various visual deficits in AD have been reported and there have been conflicting reports, through imaging and pathology studies, regarding the presence of changes in the globe that mirror Alzheimer changes in the brain. Moreover, both macular degeneration and glaucoma have been variously characterized as having AD-related features. We examined one or both eyes from 19 autopsy cases, 17 of which had varying degrees of AD-related changes, and 2 of which were age-matched controls. Three cases had glaucoma and 4 had macular degeneration. Immunohistochemistry for tau, β-amyloid, TDP-43, ubiquitin, and α-synuclein showed no evidence of inclusions, deposits or other protein accumulation in any case, in any part of the globe. This finding suggests that regardless of the severity of changes seen in the brain in AD, there are no similar changes in the globe.

scholarly journals The collagen receptor glycoprotein VI promotes platelet-mediated aggregation of β-amyloid

2020 ◽  
Vol 13 (643) ◽  
pp. eaba9872
Author(s):  
Lili Donner ◽  
Laura Mara Toska ◽  
Irena Krüger ◽  
Sandra Gröniger ◽  
Ruben Barroso ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Brain Parenchyma ◽  
Cerebral Vessels ◽  
Amyloid Angiopathy ◽  
Amyloid Aggregation ◽  
Platelet Surface ◽  
Glycoprotein Vi ◽  
Β Amyloid ◽  
Collagen Receptor ◽  
The Brain

Cerebral amyloid angiopathy (CAA) and β-amyloid (Aβ) deposition in the brain parenchyma are hallmarks of Alzheimer’s disease (AD). We previously reported that platelets contribute to Aβ aggregation in cerebral vessels by secreting the factor clusterin upon binding of Aβ40 to the fibrinogen receptor integrin αIIbβ3. Here, we investigated the contribution of the collagen receptor GPVI (glycoprotein VI) in platelet-induced amyloid aggregation. Using platelets isolated from GPVI–wild type and GPVI-deficient human donors and mice, we found that Aβ40 bound to GPVI, which induced the release of ATP and fibrinogen, resulting in platelet aggregation. Binding of Aβ40 to integrin αIIbβ3, fibrinogen, and GPVI collectively contributed to the formation of amyloid clusters at the platelet surface. Consequently, blockade of αIIbβ3 or genetic loss of GPVI reduced amyloid fibril formation in cultured platelets and decreased the adhesion of Aβ-activated platelets to injured carotid arteries in mice. Application of losartan to inhibit collagen binding to GPVI resulted in decreased Aβ40-stimulated platelet activation, factor secretion, and platelet aggregation. Furthermore, the application of GPVI- or integrin-blocking antibodies reduced the formation of platelet-associated amyloid aggregates. Our findings indicate that Aβ40 promotes platelet-mediated amyloid aggregation by binding to both GPVI and integrin αIIbβ3. Blocking these pathways may therapeutically reduce amyloid plaque formation in cerebral vessels and the brain parenchyma of patients.

scholarly journals Can Animal Models Inform on the Relationship between Depression and Alzheimer Disease?

2018 ◽  
Vol 64 (1) ◽  
pp. 18-29 ◽  
Author(s):  
Jennifer N. K. Nyarko ◽  
Maa O. Quartey ◽  
Glen B. Baker ◽  
Darrell D. Mousseau
Keyword(s):  
Animal Models ◽  
Alzheimer Disease ◽  
Disease Onset ◽  
Model Studies ◽  
Strong Indicator ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
The Relationship ◽  
Fundamental Shift ◽  
The Brain

The focus on the β-amyloid (Aβ) peptide in clinical Alzheimer disease (AD) as well as in animal models of AD has perhaps biased our understanding of what contributes to the heterogeneity in disease onset and progression. Part of this heterogeneity could reflect the various neuropsychiatric risk factors that present with common symptomatology and can predispose the brain to AD-like changes. One such risk factor is depression. Animal models, particularly mouse models carrying variants of AD-related gene(s), many of which lead to an accumulation of Aβ, suggest that a fundamental shift in depression-related monoaminergic systems (including serotonin and noradrenaline) is a strong indicator of the altered cellular function associated with the earlier(est) stages of AD-related pathology. These changes in monoaminergic neurochemistry could provide for relevant targets for intervention in clinical AD and/or could support a polypharmacy strategy, which might include the targeting of Aβ, in vulnerable populations. Future studies must also include female mice as well as male mice in animal model studies on the relationship between depression and AD.

Аnticholinesterase and antioxidant activity of new binary conjugates of (с)-carbolines

2019 ◽  
Vol 484 (1) ◽  
pp. 104-108
Author(s):  
G. F. Makhaeva ◽  
E. F. Shevtsova ◽  
N. P. Boltneva ◽  
N. V. Kovaleva ◽  
E. V. Rudakova ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Antioxidant Activity ◽  
Anticholinesterase Activity ◽  
Amyloid Aggregation ◽  
Varying Length ◽  
Β Amyloid ◽  
New Compounds

This study presents the synthesis of binary tetrohydro-γ-carbolines with ditriazol spacers of varying length, which exhibit anticholinesterase and antioxidant activity, as compared to the original Dimebon prototype. Anticholinesterase activity suggests the potential ability of the new compounds to block β-amyloid aggregation induced by anticholinesterase, making them promising candidates for further research preparations for the treatment of Alzheimer's disease. Particular attention should be paid to the conjugate with an intertriazol hexamethylene spacer, which can be regarded as the leading compound in this series.

Potential immunotherapy for Alzheimer disease and age-related dementia

2019 ◽  
Vol 21 (1) ◽  
pp. 21-25 ◽  
Keyword(s):  
Immune System ◽  
Alzheimer Disease ◽  
Cross Talk ◽  
Immune Checkpoint ◽  
Short Review ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
New Approach ◽  
Age Related ◽  
The Brain

Emerging results support the concept that Alzheimer disease (AD) and age-related dementia are affected by the ability of the immune system to contain the brain's pathology. Accordingly, well-controlled boosting, rather than suppression of systemic immunity, has been suggested as a new approach to modify disease pathology without directly targeting any of the brain's disease hallmarks. Here, we provide a short review of the mechanisms orchestrating the cross-talk between the brain and the immune system. We then discuss how immune checkpoint blockade directed against the PD-1/PD-L1 pathways could be developed as an immunotherapeutic approach to combat this disease using a regimen that will address the needs to combat AD.

Potential immunotherapy for Alzheimer disease and age-related dementia

2019 ◽  
Vol 21 (1) ◽  
pp. 21-25 ◽  
Keyword(s):  
Immune System ◽  
Alzheimer Disease ◽  
Cross Talk ◽  
Immune Checkpoint ◽  
Short Review ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
New Approach ◽  
Age Related ◽  
The Brain

Emerging results support the concept that Alzheimer disease (AD) and age-related dementia are affected by the ability of the immune system to contain the brain’s pathology. Accordingly, well-controlled boosting, rather than suppression of systemic immunity, has been suggested as a new approach to modify disease pathology without directly targeting any of the brain’s disease hallmarks. Here, we provide a short review of the mechanisms orchestrating the cross-talk between the brain and the immune system. We then discuss how immune checkpoint blockade directed against the PD-1/PD-L1 pathways could be developed as an immunotherapeutic approach to combat this disease using a regimen that will address the needs to combat AD.

scholarly journals Effect of memantine, an anti-Alzheimer’s drug, on rodent microglial cells in vitro

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Toru Murakawa-Hirachi ◽  
Yoshito Mizoguchi ◽  
Masahiro Ohgidani ◽  
Yoshinori Haraguchi ◽  
Akira Monji
Keyword(s):  
Neuronal Death ◽  
Phagocytic Activity ◽  
Microglial Cell ◽  
Cell Function ◽  
Microglial Cells ◽  
Phagocytosis Assay ◽  
Intracellular Ca ◽  
Β Amyloid ◽  
The Brain

AbstractThe pathophysiology of Alzheimer’s disease (AD) is related to neuroinflammatory responses mediated by microglia. Memantine, an antagonist of N-methyl-d-aspartate (NMDA) receptors used as an anti-Alzheimer’s drug, protects from neuronal death accompanied by suppression of proliferation and activation of microglial cells in animal models of AD. However, it remains to be tested whether memantine can directly affect microglial cell function. In this study, we examined whether pretreatment with memantine affects intracellular NO and Ca2+ mobilization using DAF-2 and Fura-2 imaging, respectively, and tested the effects of memantine on phagocytic activity by human β-Amyloid (1–42) phagocytosis assay in rodent microglial cells. Pretreatment with memantine did not affect production of NO or intracellular Ca2+ elevation induced by TNF in rodent microglial cells. Pretreatment with memantine also did not affect the mRNA expression of pro-inflammatory (TNF, IL-1β, IL-6 and CD45) or anti-inflammatory (IL-10, TGF-β and arginase) phenotypes in rodent microglial cells. In addition, pretreatment with memantine did not affect the amount of human β-Amyloid (1–42) phagocytosed by rodent microglial cells. Moreover, we observed that pretreatment with memantine did not affect 11 major proteins, which mainly function in the phagocytosis and degradation of β-Amyloid (1–42), including TREM2, DAP12 and neprilysin in rodent microglial cells. To the best of our knowledge, this is the first report to suggest that memantine does not directly modulate intracellular NO and Ca2+ mobilization or phagocytic activity in rodent microglial cells. Considering the neuroinflammation hypothesis of AD, the results might be important to understand the effect of memantine in the brain.

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