scholarly journals Alzheimer’s Disease: A Thermodynamic Perspective

2020 ◽  
Vol 10 (21) ◽  
pp. 7562
Author(s):  
Umberto Lucia ◽  
Giulia Grisolia ◽  
Thomas S. Deisboeck
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Transmission ◽  
Cyclic Nucleotide ◽  
Ion Fluxes ◽  
Thermodynamic Approach ◽  
Neuronal Membrane ◽  
Hcn Channels ◽  
K Currents

Alzheimer’s disease is investigated using a thermodynamic approach based on ion fluxes across the neuronal membrane. Our study indicates that the onset of Alzheimer’s may be aided by a hyperpolarization of this membrane, because hyperpolarization-activated cyclic nucleotide gated HCN channels 1–4 conduct inward, with the consequence of depolarising Na+/K+ currents which in turn impacts synaptic transmission and reduces plasticity.

scholarly journals The Pathological Roles of Ganglioside Metabolism in Alzheimer's Disease: Effects of Gangliosides on Neurogenesis

2011 ◽  
Vol 2011 ◽  
pp. 1-14 ◽  
Author(s):  
Toshio Ariga ◽  
Chandramohan Wakade ◽  
Robert K. Yu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Cholinergic Neurons ◽  
Cell Number ◽  
Neuronal Membrane ◽  
Amyloid Β Protein ◽  
Neuroepithelial Cells ◽  
Ganglioside Metabolism ◽  
Membrane Components

Conversion of the soluble, nontoxic amyloid β-protein (Aβ) into an aggregated, toxic form rich in β-sheets is a key step in the onset of Alzheimer's disease (AD). It has been suggested that Aβ induces changes in neuronal membrane fluidity as a result of its interactions with membrane components such as cholesterol, phospholipids, and gangliosides. Gangliosides are known to bind Aβ. A complex of GM1 and Aβ, termed “GAβ”, has been identified in AD brains. Abnormal ganglioside metabolism also may occur in AD brains. We have reported an increase of Chol-1α antigens, GQ1bα and GT1aα, in the brain of transgenic mouse AD model. GQ1bα and GT1aα exhibit high affinities to Aβs. The presence of Chol-1α gangliosides represents evidence for genesis of cholinergic neurons in AD brains. We evaluated the effects of GM1 and Aβ1–40 on mouse neuroepithelial cells. Treatment of these cells simultaneously with GM1 and Aβ1–40 caused a significant reduction of cell number, suggesting that Aβ1–40 and GM1 cooperatively exert a cytotoxic effect on neuroepithelial cells. An understanding of the mechanism on the interaction of GM1 and Aβs in AD may contribute to the development of new neuroregenerative therapies for this disorder.

Neuroprotective and Neurotrophic Efficacy of Phytoestrogens in Cultured Hippocampal Neurons

2002 ◽  
Vol 227 (7) ◽  
pp. 509-519 ◽  
Author(s):  
Lixia Zhao ◽  
Qi Chen ◽  
Roberta Diaz Brinton
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuroprotective Effect ◽  
Membrane Damage ◽  
Glutamate Excitotoxicity ◽  
Neuronal Membrane ◽  
Estrogen Replacement ◽  
17Β Estradiol ◽  
Β Amyloid ◽  
Ldh Release

Epidemiological data from retrospective and case-control studies have indicated that estrogen replacement therapy (ERT) can decrease the risk of developing Alzheimer's disease. In addition, ERT has been found to promote cellular correlates of memory and to promote neuronal survival both in vivo and in vitro. Phytoestrogens have been proposed as potential alternatives to ERT. To determine whether phytoestrogens exert estrogen agonist effect in neural tissue, investigations of neuroprotective and neurotrophic efficacy of phytoestrogens were conducted. Six phytoestrogens, genistein, genistin, daldzein, daidzin, formononetin, and equol, were tested for their neuroprotective efficacy against two toxic insults, glutamate excitotoxicity and β-amyloid25–35. Neuronal membrane damage was quantitatively measured by lactate dehydrogenase (LDH) release, and neuronal mitochondrial viability was determined by 3-[4,5-dimethylthiazoi-2-yl]-2,5-diphenyl tetrazolium bromld (MTT) assay. Results of these studies demonstrated that all phytoestrogens induced a modest but significant reduction in LDH release following exposure to glutamate and β-amyloid25–35. In contrast, none of phytoestrogens induced a significant increase in reduced MTT levels, which occurred in the presence of a full estrogen agonist, 17β-estradiol. Analysis of the neurotrophic potential of genistein and daidzein, two phytoestrogens that exerted a significant reduction in LDH release, demonstrated that neither of these molecules promoted hippocampal neuron process outgrowth. Results of these analyses indicate that although phytoestrogens exert a neuroprotective effect at the plasma membrane, they do not sustain neuron mitochondrial viability nor do they induce cellular correlates of memory as neurite outgrowth and synaptogenesis are putative mechanisms of memory. Data derived from these investigations would predict that phytoestrogens could exert some neuroprotective effects analogous to that of antioxidants, but that these molecules are not functional equivalents to endogenously active 17β-estradiol or to estrogen replacement formulations and, therefore, would raise the concern that they may not reduce the risk of Alzheimer's disease or sustain memory function in postmenopausal women.

CSF biomarkers reveal heterogeneous synaptic transmission in subgroups of Alzheimer’s disease patients

2015 ◽  
Vol 8 (2) ◽  
pp. 419-420
Author(s):  
Giacomo Koch ◽  
Francesco Di Lorenzo ◽  
Sonia Bonnì ◽  
Viviana Ponzo ◽  
Marco Bozzali ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Transmission ◽  
Csf Biomarkers

scholarly journals Potentiation of amyloid beta phagocytosis and amelioration of synaptic dysfunction upon FAAH deletion in a mouse model of Alzheimer's disease

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Gonzalo Ruiz-Pérez ◽  
Samuel Ruiz de Martín Esteban ◽  
Sharai Marqués ◽  
Noelia Aparicio ◽  
M. Teresa Grande ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Synaptic Transmission ◽  
Amyloid Beta ◽  
Molecular Mechanisms ◽  
Long Term Potentiation ◽  
Genetic Inactivation ◽  
5Xfad Mouse

Abstract Background The complex pathophysiology of Alzheimer’s disease (AD) hampers the development of effective treatments. Attempts to prevent neurodegeneration in AD have failed so far, highlighting the need for further clarification of the underlying cellular and molecular mechanisms. Neuroinflammation seems to play a crucial role in disease progression, although its specific contribution to AD pathogenesis remains elusive. We have previously shown that the modulation of the endocannabinoid system (ECS) renders beneficial effects in a context of amyloidosis, which triggers neuroinflammation. In the 5xFAD model, the genetic inactivation of the enzyme that degrades anandamide (AEA), the fatty acid amide hydrolase (FAAH), was associated with a significant amelioration of the memory deficit. Methods In this work, we use electrophysiology, flow cytometry and molecular analysis to evaluate the cellular and molecular mechanisms underlying the improvement associated to the increased endocannabinoid tone in the 5xFAD mouse− model. Results We demonstrate that the chronic enhancement of the endocannabinoid tone rescues hippocampal synaptic plasticity in the 5xFAD mouse model. At the CA3–CA1 synapse, both basal synaptic transmission and long-term potentiation (LTP) of synaptic transmission are normalized upon FAAH genetic inactivation, in a CB1 receptor (CB1R)- and TRPV1 receptor-independent manner. Dendritic spine density in CA1 pyramidal neurons, which is notably decreased in 6-month-old 5xFAD animals, is also restored. Importantly, we reveal that the expression of microglial factors linked to phagocytic activity, such as TREM2 and CTSD, and other factors related to amyloid beta clearance and involved in neuron–glia crosstalk, such as complement component C3 and complement receptor C3AR, are specifically upregulated in 5xFAD/FAAH−/− animals. Conclusion In summary, our findings support the therapeutic potential of modulating, rather than suppressing, neuroinflammation in Alzheimer’s disease. In our model, the long-term enhancement of the endocannabinoid tone triggered augmented microglial activation and amyloid beta phagocytosis, and a consequent reversal in the neuronal phenotype associated to the disease.

scholarly journals cindr, the Drosophila Homolog of the CD2AP Alzheimer’s Disease Risk Gene, Is Required for Synaptic Transmission and Proteostasis

Cell Reports ◽  
2019 ◽  
Vol 28 (7) ◽  
pp. 1799-1813.e5 ◽  
Author(s):  
Shamsideen A. Ojelade ◽  
Tom V. Lee ◽  
Nikolaos Giagtzoglou ◽  
Lei Yu ◽  
Berrak Ugur ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Transmission ◽  
Disease Risk ◽  
Risk Gene ◽  
Drosophila Homolog

Cyclic Nucleotides Signaling and Phosphodiesterase Inhibition: Defying Alzheimer’s Disease

2020 ◽  
Vol 21 (13) ◽  
pp. 1371-1384 ◽  
Author(s):  
Vivek K. Sharma ◽  
Thakur G. Singh ◽  
Shareen Singh
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cyclic Nucleotides ◽  
Cyclic Nucleotide ◽  
Phosphodiesterase Inhibitors ◽  
Physiological Status ◽  
Altered Expression ◽  
Brain Functions ◽  
Nucleotide Signaling ◽  
Camp And Cgmp

Defects in brain functions associated with aging and neurodegenerative diseases benefit insignificantly from existing options, suggesting that there is a lack of understanding of pathological mechanisms. Alzheimer’s disease (AD) is such a nearly untreatable, allied to age neurological deterioration for which only the symptomatic cure is available and the agents able to mould progression of the disease, is still far away. The altered expression of phosphodiesterases (PDE) and deregulated cyclic nucleotide signaling in AD has provoked a new thought of targeting cyclic nucleotide signaling in AD. Targeting cyclic nucleotides as an intracellular messenger seems to be a viable approach for certain biological processes in the brain and controlling substantial. Whereas, the synthesis, execution, and/or degradation of cyclic nucleotides has been closely linked to cognitive deficits. In relation to cognition, the cyclic nucleotides (cAMP and cGMP) have an imperative execution in different phases of memory, including gene transcription, neurogenesis, neuronal circuitry, synaptic plasticity and neuronal survival, etc. AD is witnessed by impairments of these basic processes underlying cognition, suggesting a crucial role of cAMP/cGMP signaling in AD populations. Phosphodiesterase inhibitors are the exclusive set of enzymes to facilitate hydrolysis and degradation of cAMP and cGMP thereby, maintains their optimum levels initiating it as an interesting target to explore. The present work reviews a neuroprotective and substantial influence of PDE inhibition on physiological status, pathological progression and neurobiological markers of AD in consonance with the intensities of cAMP and cGMP.

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