The Combined Effects of Amyloidosis and Serotonin Deficiency by Tryptophan Hydroxylase-2 Knockout Impacts Viability of the APP/PS1 Mouse Model of Alzheimer’s Disease

2021 ◽  
pp. 1-18
Author(s):  
Christian Ulrich von Linstow ◽  
Jonas Waider ◽  
Marianne Skov-Skov Bergh ◽  
Marco Anzalone ◽  
Cecilie Madsen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tryptophan Hydroxylase ◽  
Presenilin 1 ◽  
Mrna Levels ◽  
Combined Effects ◽  
Tryptophan Hydroxylase 2 ◽  
Model Of Alzheimer’S Disease ◽  
Serotonin Deficiency ◽  
Targeted Inactivation

Background: A decline of brain serotonin (5-HT) is held responsible for the changes in mood that can be observed in Alzheimer’s disease (AD). However, 5-HT’ergic signaling is also suggested to reduce the production of pathogenic amyloid-4β (Aβ). Objective: To investigate the effect of targeted inactivation of tryptophan hydroxylase-2 (Tph2), which is essential for neuronal 5-HT synthesis, on amyloidosis in amyloid precursor protein (APP)swe/presenilin 1 (PS1) ΔE9 transgenic mice. Methods: Triple-transgenic (3xTg) APP/PS1 mice with partial (+/-) or complete Tph2 knockout (–/–) were allowed to survive until 6 months old with APP/PS1, Tph2–/–, and wildtype mice. Survival and weight were recorded. Levels of Aβ 42/40/38, soluble APPα (sAβPPα) and sAβPPβ, and cytokines were analyzed by mesoscale, neurotransmitters by mass spectrometry, and gene expression by quantitative PCR. Tph2, microglia, and Aβ were visualized histologically. Results: Tph2 inactivation in APP/PS1 mice significantly reduced viability, without impacting soluble and insoluble Aβ 42 and Aβ 40 in neocortex and hippocampus, and with only mild changes of soluble Aβ 42/Aβ 40. However, sAβPPα and sAβPPβ in hippocampus and Aβ 38 and Aβ 40 in cerebrospinal fluid were reduced. 3xTg–/–mice were devoid of Tph2 immunopositive fibers and 5-HT. Cytokines were unaffected by genotype, as were neocortical TNF, HTR2a and HTR2b mRNA levels in Tph2–/– mice. Microglia clustered around Aβ plaques regardless of genotype. Conclusion: The results suggest that Tph2 inactivation influences AβPP processing, at least in the hippocampus, although levels of Aβ are unchanged. The reduced viability of 3xTg–/–mice could indicate that 5-HT protects against the seizures that can impact the viability of APP/PS1 mice.

scholarly journals Prostaglandin EP2 receptor antagonist ameliorates neuroinflammation in a two-hit mouse model of Alzheimer’s disease

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Avijit Banik ◽  
Radhika Amaradhi ◽  
Daniel Lee ◽  
Michael Sau ◽  
Wenyi Wang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Complete Blood Count ◽  
Cardiovascular Effects ◽  
Mrna Levels ◽  
Proinflammatory Mediators ◽  
Model Of Alzheimer’S Disease ◽  
Cox 2 ◽  
5Xfad Mice

Abstract Background Alzheimer’s disease (AD) causes substantial medical and societal burden with no therapies ameliorating cognitive deficits. Centralized pathologies involving amyloids, neurofibrillary tangles, and neuroinflammatory pathways are being investigated to identify disease-modifying targets for AD. Cyclooxygenase-2 (COX-2) is one of the potential neuroinflammatory agents involved in AD progression. However, chronic use of COX-2 inhibitors in patients produced adverse cardiovascular effects. We asked whether inhibition of EP2 receptors, downstream of the COX-2 signaling pathway, can ameliorate neuroinflammation in AD brains in presence or absence of a secondary inflammatory stimuli. Methods We treated 5xFAD mice and their non-transgenic (nTg) littermates in presence or absence of lipopolysaccharide (LPS) with an EP2 antagonist (TG11-77.HCl). In cohort 1, nTg (no-hit) or 5xFAD (single-hit—genetic) mice were treated with vehicle or TG11-77.HCl for 12 weeks. In cohort 2, nTg (single-hit—environmental) and 5xFAD mice (two-hit) were administered LPS (0.5 mg/kg/week) and treated with vehicle or TG11-77.HCl for 8 weeks. Results Complete blood count analysis showed that LPS induced anemia of inflammation in both groups in cohort 2. There was no adverse effect of LPS or EP2 antagonist on body weight throughout the treatment. In the neocortex isolated from the two-hit cohort of females, but not males, the elevated mRNA levels of proinflammatory mediators (IL-1β, TNF, IL-6, CCL2, EP2), glial markers (IBA1, GFAP, CD11b, S110B), and glial proteins were significantly reduced by EP2 antagonist treatment. Intriguingly, the EP2 antagonist had no effect on either of the single-hit cohorts. There was a modest increase in amyloid–plaque deposition upon EP2 antagonist treatment in the two-hit female brains, but not in the single-hit genetic female cohort. Conclusion These results reveal a potential neuroinflammatory role for EP2 in the two-hit 5xFAD mouse model. A selective EP2 antagonist reduces inflammation only in female AD mice subjected to a second inflammatory insult.

scholarly journals Neuroprotective Effect ofBrassica oleraceaSprouts Crude Juice in a Cellular Model of Alzheimer’s Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-17 ◽  
Author(s):  
Alessandra Masci ◽  
Roberto Mattioli ◽  
Paolo Costantino ◽  
Simona Baima ◽  
Giorgio Morelli ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Phenolic Compounds ◽  
Chromatin Condensation ◽  
Amyloid Peptide ◽  
Antioxidant Compounds ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Mrna Levels ◽  
Model Of Alzheimer’S Disease

β-Amyloid peptide (Aβ) aberrant production and aggregation are major factors implicated in the pathogenesis of Alzheimer’s disease (AD), causing neuronal deathviaoxidative stress. Several studies have highlighted the importance of polyphenolic antioxidant compounds in the treatment of AD, but complex food matrices, characterized by a different relative content of these phytochemicals, have been neglected. In the present study, we analyzed the protective effect on SH-SY5Y cells treated with the fragment Aβ25–35by two crude juices of broccoli sprouts containing different amounts of phenolic compounds as a result of different growth conditions. Both juices protected against Aβ-induced cytotoxicity and apoptotic cell death as evidenced by cell viability, nuclear chromatin condensation, and apoptotic body formation measurements. These effects were mediated by the modulation of the mitochondrial function and of theHSP70gene transcription and expression. Furthermore, the juices upregulated the intracellular glutathione content and mRNA levels or activity of antioxidant enzymes such as heme oxygenase-1, thioredoxin, thioredoxin reductase, and NAD(P)H:quinone oxidoreductase 1viaactivation of NF-E2-related factor 2 (Nrf2). Although the effects of the two juices were similar, the juice enriched in phenolic compounds showed a greater efficacy in inducing the activation of the Nrf2 signalling pathway.

Evidence for the involvement of calbindin D28k in the presenilin 1 model of Alzheimer's disease

Neuroscience ◽  
2010 ◽  
Vol 169 (1) ◽  
pp. 532-543 ◽  
Author(s):  
G.L. Odero ◽  
K. Oikawa ◽  
K.A.C. Glazner ◽  
J. Schapansky ◽  
D. Grossman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Presenilin 1 ◽  
Model Of Alzheimer’S Disease ◽  
Calbindin D28k

scholarly journals AstroDot: a new method for studying the spatial distribution of mRNA in astrocytes

2019 ◽  
Author(s):  
Marc Oudart ◽  
Romain Tortuyaux ◽  
Philippe Mailly ◽  
Noémie Mazaré ◽  
Anne-Cécile Boulay ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Large Subunit ◽  
Three Dimensional ◽  
R Package ◽  
New Method ◽  
Mrna Levels ◽  
Model Of Alzheimer’S Disease ◽  
Confocal Images ◽  
Amyloid Aβ

AbstractCells with a complex shape often use mRNA distribution and local translation to regulate distal functions. These mechanisms have recently been described in astrocytes, the processes of which contact and functionally modulate neighbouring synapses and blood vessels. In order to study the distribution of mRNA in astrocytes, we developed a three-dimensional histological method that combines mRNA detection viain situhybridization with immunostaining of the astrocyte-specific intermediate filament glial fibrillary acidic protein (GFAP). Three-dimensional confocal images were analyzed using AstroDot, a custom Image J plug-in developed in-house for the identification and quantification of mRNAs in GFAP-immunolabelled astrocyte somata, large processes and fine processes. The custom R package AstroStat was used to analyze the AstroDot results. Taking the characterization of mRNAs encoding the astrocyte-specific GFAP α and δ isoforms in the hippocampus as a proof of concept, we showed thatGfapα andGfapδ mRNAs mainly colocalized with GFAP in astrocyte processes.Gfapα mRNA was more abundant thanGfapδ mRNA, and was predominantly found in fine processes. Upon glial activation in the APPswe/PS1dE9 mouse model of Alzheimer’s disease, the same overall patterns were found but we noted strong variations inGfapα andGfapδ mRNA density and distribution as a function of the part of the hippocampus and the astrocyte’s proximity to beta-amyloid (Aβ) plaques. In astrocytes not associated with Aβ, Gfap α mRNA levels were only slightly elevated, and Gfap δ mRNA was distributed within the fine processes; these effects were more prominent in CA3 than in CA1. In contrast, levels of both mRNAs were markedly elevated in the fine processes of Aβ-associated astrocytes in both CA1 and CA3. In order to validate our new method, we confirmed thatRpl4mRNA (a ubiquitously expressed mRNA encoding the large subunit ribosomal protein 4) was present in large and fine processes in both astrocytes and microglia. In summary, we have developed a novel, reliable set of tools for characterizing mRNA densities and distributions in the somata and processes of astrocytes and microglia in physiological or pathological settings. Furthermore, our results suggest that intermediate filaments are crucial for distributing mRNA within astrocytes and for modulating specificGfapmRNA profiles in Alzheimer’s disease.

scholarly journals Cotinine and 6-Hydroxy-L-Nicotine Reverses Memory Deficits and Reduces Oxidative Stress in Aβ25-35-Induced Rat Model of Alzheimer’s Disease

Antioxidants ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 768 ◽  
Author(s):  
Razvan Stefan Boiangiu ◽  
Marius Mihasan ◽  
Dragos Lucian Gorgan ◽  
Bogdan Alexandru Stache ◽  
Brindusa Alina Petre ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rat Model ◽  
Nicotinic Acetylcholine Receptors ◽  
Binding Potential ◽  
Mrna Levels ◽  
Model Of Alzheimer’S Disease ◽  
The Impact

The nicotinic derivatives, cotinine (COT), and 6-hydroxy-L-nicotine (6HLN), showed promising cognitive-improving effects without exhibiting the nicotine’s side-effects. Here, we investigated the impact of COT and 6HLN on memory impairment and the oxidative stress in the Aβ25-35-induced rat model of Alzheimer’s disease (AD). COT and 6HLN were chronically administered to Aβ25-35-treated rats, and their memory performances were assessed using in vivo tasks (Y-maze, novel object recognition, and radial arm maze). By using in silico tools, we attempted to associate the behavioral outcomes with the calculated binding potential of these nicotinic compounds in the allosteric sites of α7 and α4β2 subtypes of the nicotinic acetylcholine receptors (nAChRs). The oxidative status and acetylcholinesterase (AChE) activity were determined from the hippocampal tissues. RT-qPCR assessed bdnf, arc, and il-1β mRNA levels. Our data revealed that COT and 6HLN could bind to α7 and α4β2 nAChRs with similar or even higher affinity than nicotine. Consequently, the treatment exhibited a pro-cognitive, antioxidant, and anti-AChE profile in the Aβ25-35-induced rat model of AD. Finally, RT-qPCR analysis revealed that COT and 6HLN positively modulated the bdnf, arc, and il-1β genes expression. Therefore, these nicotinic derivatives that act on the cholinergic system might represent a promising choice to ameliorate AD conditions.

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