Adrenergic mechanisms of myocardium contractility regulation in genetic model of Alzheimer’s disease

Aim. Study is aimed to investigate contractility impairments and receptor mechanisms of adrenergic regulation of myocardium inotropic function in Alzheimer’s disease model on transgenic mice.Methods. Experiments were performed on isolated preparations of atria and ventricles myocardium of mice. Transgenic mice of B6C3-Tg(APP695)85Dbo Tg(PSENI)85Dbo genotype were used as animal model of Alzheimer’s disease. Contractile responses of myocardium were registered by conventional myographic technique in isometric conditions. To evaluate the expression of adrenergic receptors, immunofluorescence staining of myocardium with specific antibodies was performed.Results. Transgenic mice showed not only a decreased effect of norepinephrine on myocardium inotropic function but also the inversion of the effect of norepinephrine - the use of 10-5-10-4 M of norepinephrine decreased myocardium inotropic function. Immunofluorescent staining showed decrease of expression of β1- and especially β2-adrenergic receptors ventricular myocardium of transgenic mice comparing to wild type mice. Adrenergic deregulation was registered in ventricles, but not in atria. The features of adrenergic regulatory mechanisms of myocardial contractility in transgenic APP/PS1 mice aged 8-10 months are specific, although somewhat similar to wild type mice aged 8-10 months, and are evidently due to Alzheimer’s disease. The inversion of norepinephrine inotropic effect (from positive to negative) may be explained by switching the intracellular cascade pathway of β2-adrenergic receptors effects to another type of G-protein.Conclusion. The results indicate that peripheral adrenergic mechanisms of myocardial contractility regulation are impaired in studied transgenic mice model of Alzheimer’s disease. Obtained data widen our understanding of Alzheimer’s disease pathogenesis, as well as our conception of relations between cardiovascular diseases and neurodegeneration.

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Ablation of the Locus Coeruleus Increases Oxidative Stress in Tg-2576 Transgenic but Not Wild-Type Mice

International Journal of Alzheimer s Disease ◽

10.4061/2010/864625 ◽

2010 ◽

Vol 2010 ◽

pp. 1-13 ◽

Cited By ~ 1

Author(s):

Orest Hurko ◽

Kurt Boudonck ◽

Cathleen Gonzales ◽

Zoe A. Hughes ◽

J. Steve Jacobsen ◽

...

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transgenic Mice ◽

Locus Coeruleus ◽

Intermediary Metabolism ◽

Wild Type ◽

Model Of Alzheimer’S Disease ◽

Markers Of Oxidative Stress ◽

Mutant Forms

Mice transgenic for production of excessive or mutant forms of beta-amyloid differ from patients with Alzheimer's disease in the degree of inflammation, oxidative damage, and alteration of intermediary metabolism, as well as the paucity or absence of neuronal atrophy and cognitive impairment. Previous observers have suggested that differences in inflammatory response reflect a discrepancy in the state of the locus coeruleus (LC), loss of which is an early change in Alzheimer's disease but which is preserved in the transgenic mice. In this paper, we extend these observations by examining the effects of the LC on markers of oxidative stress and intermediary metabolism. We compare four groups: wild-type or Tg2576 A transgenic mice injected with DSP4 or vehicle. Of greatest interest were metabolites different between ablated and intact transgenics, but not between ablated and intact wild-type animals. The Tg2576_DSP4 mice were distinguished from the other three groups by oxidative stress and altered energy metabolism. These observations provide further support for the hypothesis that Tg2576 A transgenic mice with this ablation may be a more congruent model of Alzheimer's disease than are transgenics with an intact LC.

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Pharmacological ablation of astrocytes reduces Aβ degradation and synaptic connectivity in an ex vivo model of Alzheimer’s disease

Journal of Neuroinflammation ◽

10.1186/s12974-021-02117-y ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Nicola Davis ◽

Bibiana C. Mota ◽

Larissa Stead ◽

Emily O. C. Palmer ◽

Laura Lombardero ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Culture Media ◽

Ex Vivo ◽

Wild Type ◽

Insulin Degrading Enzyme ◽

Ex Vivo Model ◽

Model Of Alzheimer’S Disease ◽

Aβ Clearance ◽

5Xfad Mice

Abstract Background Astrocytes provide a vital support to neurons in normal and pathological conditions. In Alzheimer’s disease (AD) brains, reactive astrocytes have been found surrounding amyloid plaques, forming an astrocytic scar. However, their role and potential mechanisms whereby they affect neuroinflammation, amyloid pathology, and synaptic density in AD remain unclear. Methods To explore the role of astrocytes on Aβ pathology and neuroinflammatory markers, we pharmacologically ablated them in organotypic brain culture slices (OBCSs) from 5XFAD mouse model of AD and wild-type (WT) littermates with the selective astrocytic toxin L-alpha-aminoadipate (L-AAA). To examine the effects on synaptic circuitry, we measured dendritic spine number and size in OBCSs from Thy-1-GFP transgenic mice incubated with synthetic Aβ42 or double transgenics Thy-1-GFP/5XFAD mice treated with LAAA or vehicle for 24 h. Results Treatment of OBCSs with L-AAA resulted in an increased expression of pro-inflammatory cytokine IL-6 in conditioned media of WTs and 5XFAD slices, associated with changes in microglia morphology but not in density. The profile of inflammatory markers following astrocytic loss was different in WT and transgenic cultures, showing reductions in inflammatory mediators produced in astrocytes only in WT sections. In addition, pharmacological ablation of astrocytes led to an increase in Aβ levels in homogenates of OBCS from 5XFAD mice compared with vehicle controls, with reduced enzymatic degradation of Aβ due to lower neprilysin and insulin-degrading enzyme (IDE) expression. Furthermore, OBSCs from wild-type mice treated with L-AAA and synthetic amyloid presented 56% higher levels of Aβ in culture media compared to sections treated with Aβ alone, concomitant with reduced expression of IDE in culture medium, suggesting that astrocytes contribute to Aβ clearance and degradation. Quantification of hippocampal dendritic spines revealed a reduction in their density following L-AAA treatment in all groups analyzed. In addition, pharmacological ablation of astrocytes resulted in a decrease in spine size in 5XFAD OBCSs but not in OBCSs from WT treated with synthetic Aβ compared to vehicle control. Conclusions Astrocytes play a protective role in AD by aiding Aβ clearance and supporting synaptic plasticity.

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Detecting Amyloid-β Accumulation via Immunofluorescent Staining in a Mouse Model of Alzheimer's Disease

Journal of Visualized Experiments ◽

10.3791/62254 ◽

2021 ◽

Author(s):

Zijian Song ◽

Miao Zheng ◽

Jiahui Ding ◽

Yidi Xu ◽

Miao-Jin Ji ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Immunofluorescent Staining ◽

Model Of Alzheimer’S Disease

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P1-031: Age-related cerebral changes of brain-derived neurotrophic factor in a model of Alzheimer's disease in APP23 transgenic mice

Alzheimer s & Dementia ◽

10.1016/j.jalz.2006.05.406 ◽

2006 ◽

Vol 2 ◽

pp. S103-S103

Author(s):

Olaf Schulte-Herbrüggen ◽

Uwe Deicke ◽

Uwe Otten ◽

Dorothee Abramowski ◽

Matthias Staufenbiel ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transgenic Mice ◽

Neurotrophic Factor ◽

Brain Derived Neurotrophic Factor ◽

Model Of Alzheimer’S Disease ◽

Age Related

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A fragment of cell adhesion molecule L1 reduces amyloid-β plaques in a mouse model of Alzheimer’s disease

Cell Death and Disease ◽

10.1038/s41419-021-04348-6 ◽

2022 ◽

Vol 13 (1) ◽

Author(s):

Junkai Hu ◽

Stanley Li Lin ◽

Melitta Schachner

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cell Adhesion ◽

Adhesion Molecule ◽

Cell Adhesion Molecule ◽

Transforming Growth Factor ◽

Amyloid Β ◽

Wild Type ◽

Model Of Alzheimer’S Disease ◽

Cell Adhesion Molecule L1

AbstractDeposition of amyloid-β (Aβ) in the brain is one of the important histopathological features of Alzheimer’s disease (AD). Previously, we reported a correlation between cell adhesion molecule L1 (L1) expression and the occurrence of AD, but its relationship was unclear. Here, we report that the expression of L1 and a 70 kDa cleavage product of L1 (L1-70) was reduced in the hippocampus of AD (APPswe) mice. Interestingly, upregulation of L1-70 expression in the hippocampus of 18-month-old APPswe mice, by parabiosis involving the joining of the circulatory system of an 18-month-old APPswe mouse with a 2-month-old wild-type C57BL/6 mouse, reduced amyloid plaque deposition. Furthermore, the reduction was accompanied by the appearance of a high number of activated microglia. Mechanistically, we observed that L1-70 could combine with topoisomerase 1 (Top1) to form a complex, L1-70/Top1, that was able to regulate expression of macrophage migration inhibitory factor (MIF), resulting in the activation of microglia and reduction of Aβ plaques. Also, transforming growth factor β1 (TGFβ-1) transferred from the blood of young wild-type C57BL/6 mice to the aged AD mice, was identified as a circulating factor that induces full-length L1 and L1-70 expression. All together, these findings suggest that L1-70 contributes to the clearance of Aβ in AD, thereby adding a novel perspective in understanding AD pathogenesis.

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Arginase Inhibition Supports Survival and Differentiation of Neuronal Precursors in Adult Alzheimer’s Disease Mice

International Journal of Molecular Sciences ◽

10.3390/ijms21031133 ◽

2020 ◽

Vol 21 (3) ◽

pp. 1133 ◽

Cited By ~ 3

Author(s):

Baruh Polis ◽

Kolluru D. Srikanth ◽

Vyacheslav Gurevich ◽

Naamah Bloch ◽

Hava Gil-Henn ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transgenic Mice ◽

Adult Neurogenesis ◽

Progenitor Cell ◽

Molecular Mechanisms ◽

Neuronal Cell ◽

Cell Number ◽

Wild Type ◽

Newborn Neuron

Adult neurogenesis is a complex physiological process, which plays a central role in maintaining cognitive functions, and consists of progenitor cell proliferation, newborn cell migration, and cell maturation. Adult neurogenesis is susceptible to alterations under various physiological and pathological conditions. A substantial decay of neurogenesis has been documented in Alzheimer’s disease (AD) patients and animal AD models; however, several treatment strategies can halt any further decline and even induce neurogenesis. Our previous results indicated a potential effect of arginase inhibition, with norvaline, on various aspects of neurogenesis in triple-transgenic mice. To better evaluate this effect, we chronically administered an arginase inhibitor, norvaline, to triple-transgenic and wild-type mice, and applied an advanced immunohistochemistry approach with several biomarkers and bright-field microscopy. Remarkably, we evidenced a significant reduction in the density of neuronal progenitors, which demonstrate a different phenotype in the hippocampi of triple-transgenic mice as compared to wild-type animals. However, norvaline showed no significant effect upon the progenitor cell number and constitution. We demonstrated that norvaline treatment leads to an escalation of the polysialylated neuronal cell adhesion molecule immunopositivity, which suggests an improvement in the newborn neuron survival rate. Additionally, we identified a significant increase in the hippocampal microtubule-associated protein 2 stain intensity. We also explore the molecular mechanisms underlying the effects of norvaline on adult mice neurogenesis and provide insights into their machinery.

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P1-080: STUDY OF DAILY ORAL GENISTEIN ON SPATIAL AND OLFACTORY MEMORY IN WILD TYPE AND TRANSGENIC MICE THAT MODEL ALZHEIMER'S DISEASE

Alzheimer s & Dementia ◽

10.1016/j.jalz.2018.06.082 ◽

2006 ◽

Vol 14 (7S_Part_5) ◽

pp. P301-P302

Author(s):

Alyson C. Williamson ◽

Hayley R. LeBlanc ◽

Brian G. Gentry ◽

Craige C. Wrenn

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transgenic Mice ◽

Wild Type ◽

Olfactory Memory

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Bupropion and Citalopram in the APP23 Mouse Model of Alzheimer's Disease: A Study in a Dry-Land Maze

International Journal of Alzheimer s Disease ◽

10.1155/2012/673584 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Katharina L. Neumeister ◽

Matthias W. Riepe

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Spatial Learning ◽

Transgenic Animals ◽

Transgenic Animal ◽

Wild Type ◽

Dry Land ◽

Psychomotor Activity ◽

Model Of Alzheimer’S Disease ◽

Resting Time

Background. Incipient Alzheimer's disease is often disguised as depressive disorder. Over the course of AD, depressive symptoms are even more frequent. Hence, treatment with antidepressants is common in AD. It was the goal of the present study to assess whether two common antidepressants with different mechanisms of action affect spatial learning in a transgenic animal model of Alzheimer's disease.Methods. We assessed spatial memory of male wild-type and B6C3-Tg(APPswe,PSEN1dE9)85Dbo (APP23) transgenic animals in a complex dry-land maze. Animals were treated with citalopram (10 mg/kg) and bupropion (20 mg/kg).Results. Moving and resting time until finding the goal zone decreased in 4.5-month-old sham-treated wild-type animals and, to a lesser extent, in APP23 animals. Compared with sham-treated APP23 animals, treatment with bupropion reduced resting time and increased speed. On treatment with citalopram, moving and resting time were unchanged but speed decreased. Length of the path to the goal zone did not change on either bupropion or citalopram.Conclusion. Bupropion increases psychomotor activity in APP23 transgenic animals, while citalopram slightly reduces psychomotor activity. Spatial learning per se is unaffected by treatment with either bupropion or citalopram.

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