scholarly journals miR-132 regulates the expression of synaptic proteins in APP/PS1 transgenic mice through C1q

2019 ◽  
Vol 63 (2) ◽  
Author(s):  
Nan Xu ◽  
Ang-Di Li ◽  
Li-Li Ji ◽  
Yao Ye ◽  
Zhen-Yu Wang ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cognitive Abilities ◽  
Early Stage ◽  
Amyloid Β ◽  
In Silico Analysis ◽  
Synaptic Proteins ◽  
Downstream Target ◽  
Key Factor ◽  
The Central Nervous System ◽  
Synapse Degeneration

Cognitive impairment in Alzheimer’s disease (AD) is usually accompanied by synaptic loss in both the hippocampus and neocortex. In the early stage of AD, amyloid β-induced synapse changes is the main reason, while in the later stage, the accumulation of Tau protein promotes synapse degeneration as the key factor leading to dementia. MicroRNA (miRNA) is closely related to the expression changes of many AD-related genes. One of the most abundant brain-enriched miRNAs is miR-132, which has been shown to regulate both neuron morphogenesis and plasticity. It has been reported that miR-132 is significantly reduced in the brains of Alzheimer’s patients. Genetic deletion of miR-132 in mice promotes Aβ deposition, leading to impaired memory and enhanced Tau pathology, but how the miRNA-mediated gene expression dysregulation contributes to AD pathology remains unclear. Here we found the possible downstream target of miR-132 by in silico analysis, namely C1q. C1q is the primary protein of classical complement cascade, which is highly expressed in the synaptic regions of the central nervous system in Alzheimer’s patients. However, it is not clear whether miR-132 plays a role in AD through regulating C1q. To address this question, the APP/PS1 transgenic mice were transfected with miR-132 and given C1 inhibitors. Behavior tests were conducted to assess memory and cognitive abilities seven days after administration. In addition, we analyzed the expression of PSD95, Synapsin-1 and phosphorylated (p)-Synapsin. We found that the expression levels of the synaptic proteins treated with miR-132 or C1INH were significantly increased compared with the AD group. Further RT-qPCR result suggested that miR-132 might regulate C1q expression in AD.

scholarly journals Distinct microglial response against Alzheimer's amyloid and tau pathologies characterized by P2Y12 receptor

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Jun Maeda ◽  
Takeharu Minamihisamatsu ◽  
Masafumi Shimojo ◽  
Xiaoyun Zhou ◽  
Maiko Ono ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Receptor Gene ◽  
Amyloid Β ◽  
Progressive Increase ◽  
P2y12 Receptor ◽  
Down Regulation ◽  
Disease Etiology ◽  
The Central Nervous System

Abstract Microglia are the resident phagocytes of the central nervous system, and microglial activation is considered to play an important role in the pathogenesis of neurodegenerative diseases. Recent studies with single-cell RNA analysis of CNS cells in Alzheimer’s disease and diverse other neurodegenerative conditions revealed that the transition from homeostatic microglia to disease-associated microglia was defined by changes of gene expression levels, including down-regulation of the P2Y12 receptor gene (P2Y12R). However, it is yet to be clarified in Alzheimer’s disease brains whether and when this down-regulation occurs in response to amyloid-β and tau depositions, which are core pathological processes in the disease etiology. To further evaluate the significance of P2Y12 receptor alterations in the neurodegenerative pathway of Alzheimer’s disease and allied disorders, we generated an anti-P2Y12 receptor antibody and examined P2Y12 receptor expressions in the brains of humans and model mice bearing amyloid-β and tau pathologies. We observed that the brains of both Alzheimer’s disease and non-Alzheimer’s disease tauopathy patients and tauopathy model mice (rTg4510 and PS19 mouse lines) displayed declined microglial P2Y12 receptor levels in regions enriched with tau inclusions, despite an increase in the total microglial population. Notably, diminution of microglial immunoreactivity with P2Y12 receptor was noticeable prior to massive accumulations of phosphorylated tau aggregates and neurodegeneration in rTg4510 mouse brains, despite a progressive increase of total microglial population. On the other hand, Iba1-positive microglia encompassing compact and dense-cored amyloid-β plaques expressed P2Y12 receptor at varying levels in amyloid precursor protein (APP) mouse models (APP23 and AppNL-F/NL-F mice). By contrast, neuritic plaques in Alzheimer’s disease brains were associated with P2Y12 receptor-negative microglia. These data suggest that the down-regulation of microglia P2Y12 receptor, which is characteristic of disease-associated microglia, is intimately associated with tau rather than amyloid-β pathologies from an early stage and could be a sensitive index for neuroinflammatory responses to Alzheimer’s disease-related neurodegenerative processes.

Hypoxic Preconditioning Ameliorates Amyloid-β Pathology and Longterm Cognitive Decline in AβPP/PS1 Transgenic Mice

2020 ◽  
Vol 17 (7) ◽  
pp. 626-634
Author(s):  
Jian Zhang ◽  
Ji Zhang ◽  
Xiao-Jia Li ◽  
Jun Xiao ◽  
Fang Ye
Keyword(s):  
Transgenic Mice ◽  
Amyloid Β ◽  
Hypoxic Preconditioning ◽  
Substantial Evidence ◽  
Memory Decline ◽  
Protein Levels ◽  
Promising Strategy ◽  
The Central Nervous System ◽  
Ischemic Diseases ◽  
Neuroadaptive Changes

Background and Objective: Hypoxic Preconditioning (HPC) has been well established to trigger endogenous mechanisms of neuroprotection basing on models of hypoxic and ischemic diseases in the Central Nervous System (CNS). However, its effects against Alzheimer's Disease (AD) still lack substantial evidence and in-depth exploration. The present study aimed to investigate the impacts of HPC on AD-related memory decline and amyloid-β (Aβ) pathology in AβPP/PS1 transgenic mice. Methods: Seven-week-old AβPP/PS1 transgenic mice were randomized into HPC and non-HPC groups. The HPC groups were treated with early and repetitive HPC for four weeks, while the non-HPC group was raised under normoxia condition. All the animals were then raised until the age of 28 weeks when Morris water maze tests were conducted to examine the animals’ spatial memory. Indicators for Aβ pathology (soluble Aβ levels and numbers of Aβ plaques) and the expression of relevant proteins were measured to explore potential mechanisms. Results: The results showed that HPC ameliorated memory decline and Aβ pathology in AβPP/PS1 mice. The protein levels of Amyloid-β Precursor Protein (AβPP) and β-site APP Cleaving Enzyme 1 (BACE1) were reduced while that of Hypoxic inducible factor 1α (HIF-1α) was elevated in HPC groups. Conclusion: HPC might be a promising strategy for AD intervention. Its potential protection might be realized via downregulating the expressions of AβPP and BACE1 and hence inhibiting Aβ pathology. Notably, HIF-1α might play a key role in mediating subsequent neuroadaptive changes following HPC.

scholarly journals Breaking the Cycle, Cholesterol Cycling, and Synapse Damage in Response to Amyloid-β

2017 ◽  
Vol 11 ◽  
pp. 117906951773309 ◽  
Author(s):  
Clive Bate
Keyword(s):  
Cholesterol Ester ◽  
Prion Proteins ◽  
Amyloid Β ◽  
Cholesterol Esterification ◽  
Signalling Pathways ◽  
Aβ Oligomers ◽  
Key Factor ◽  
Key Driver ◽  
Synapse Degeneration ◽  
Ester Hydrolases

Soluble amyloid-β (Aβ) oligomers, a key driver of pathogenesis in Alzheimer disease, bind to cellular prion proteins (PrPC) expressed on synaptosomes resulting in increased cholesterol concentrations, movement of cytoplasmic phospholipase A2 (cPLA2) to lipid rafts and activation of cPLA2. The formation of Aβ-PrPC-cPLA2 complexes was controlled by the cholesterol ester cycle. Thus, Aβ activated cholesterol ester hydrolases which released cholesterol from stores of cholesterol esters; the increased cholesterol concentrations stabilised Aβ-PrPC-cPLA2 complexes. Conversely, cholesterol esterification reduced cholesterol concentrations causing the dispersal of Aβ-PrPC-cPLA2. In cultured neurons, the cholesterol ester cycle regulated Aβ-induced synapse damage; inhibition of cholesterol ester hydrolases protected neurons, whereas inhibition of cholesterol esterification increased the Aβ-induced synapse damage. Here, I speculate that a failure to deactivate signalling pathways can lead to pathology. Consequently, the esterification of cholesterol is a key factor in the dispersal of Aβ-induced signalling platforms and synapse degeneration.

Sialylated glycosylphosphatidylinositols suppress the production of toxic amyloid-β oligomers

2017 ◽  
Vol 474 (17) ◽  
pp. 3045-3058 ◽  
Author(s):  
William Nolan ◽  
Harriet McHale-Owen ◽  
Clive Bate
Keyword(s):  
Cell Model ◽  
Amyloid Β ◽  
Critical Factor ◽  
Cellular Prion Protein ◽  
Progressive Dementia ◽  
Aβ Oligomers ◽  
Key Factor ◽  
A Cell ◽  
Synapse Degeneration ◽  
Soluble Aβ Oligomers

The production of amyloid-β (Aβ) is a key factor driving pathogenesis in Alzheimer's disease (AD). Increasing concentrations of soluble Aβ oligomers within the brain lead to synapse degeneration and the progressive dementia characteristic of AD. Since Aβ exists in both disease-relevant (toxic) and non-toxic forms, the factors that affected the release of toxic Aβ were studied in a cell model. 7PA2 cells expressing the human amyloid precursor protein released Aβ oligomers that caused synapse damage when incubated with cultured neurones. These Aβ oligomers had similar potency to soluble Aβ oligomers derived from the brains of Alzheimer's patients. Although the conditioned media from 7PA2 cells treated with the cellular prion protein (PrPC) contained Aβ, it did not cause synapse damage. The loss of toxicity was associated with a reduction in Aβ oligomers and an increase in Aβ monomers. The suppression of toxic Aβ release was dependent on the glycosylphosphatidylinositol (GPI) anchor attached to PrPC, and treatment of cells with specific GPIs alone reduced the production of toxic Aβ. The efficacy of GPIs was structure-dependent and the presence of sialic acid was critical. The conditioned medium from GPI-treated cells protected neurones against Aβ oligomer-induced synapse damage; neuroprotection was mediated by Aβ monomers. These studies support the hypothesis that the ratio of Aβ monomers to Aβ oligomers is a critical factor that regulates synapse damage.

Berberine Alleviates Amyloid-beta Pathogenesis Via Activating LKB1/AMPK Signaling in the Brain of APP/PS1 Transgenic Mice

2019 ◽  
Vol 19 (5) ◽  
pp. 342-348 ◽  
Author(s):  
Zhi-You Cai ◽  
Chuan-Ling Wang ◽  
Tao-Tao Lu ◽  
Wen-Ming Yang
Keyword(s):  
Transgenic Mice ◽  
Western Blotting ◽  
Amyloid Β ◽  
Adenosine Monophosphate ◽  
Camp Response Element Binding ◽  
Enzyme Linked Immunosorbent Assay ◽  
Synaptic Density ◽  
Ampk Signaling ◽  
The Brain ◽  
Post Synaptic Density

Background:Liver kinase B1 (LKB1)/5’-adenosine monophosphate-activated protein kinase (AMPK) signaling, a metabolic checkpoint, plays a neuro-protective role in the pathogenesis of Alzheimer’s disease (AD). Amyloid-β (Aβ) acts as a classical biomarker of AD. The aim of the present study was to explore whether berberine (BBR) activates LKB1/AMPK signaling and ameliorates Aβ pathology.Methods:The Aβ levels were detected using enzyme-linked immunosorbent assay and immunohistochemistry. The following biomarkers were measured by Western blotting: phosphorylated (p-) LKB1 (Ser334 and Thr189), p-AMPK (AMPKα and AMPKβ1), synaptophysin, post-synaptic density protein 95 and p-cAMP-response element binding protein (p-CREB). The glial fibrillary acidic protein (GFAP) was determined using Western blotting and immunohistochemistry.Results:BBR inhibited Aβ expression in the brain of APP/PS1 mice. There was a strong up-regulation of both p-LKB1 (Ser334 and Thr189) and p-AMPK (AMPKα and AMPKβ1) in the brains of APP/PS1 transgenic mice after BBR-treatment (P<0.01). BBR promoted the expression of synaptophysin, post-synaptic density protein 95 and p-CREB(Ser133) in the AD brain, compared with the model mice.Conclusion:BBR alleviates Aβ pathogenesis and rescues synapse damage via activating LKB1/AMPK signaling in the brain of APP/PS1 transgenic mice.

Resveratrol Rescues Tau-Induced Cognitive Deficits and Neuropathology in a Mouse Model of Tauopathy

2019 ◽  
Vol 16 (8) ◽  
pp. 710-722 ◽  
Author(s):  
Xiao-Ying Sun ◽  
Quan-Xiu Dong ◽  
Jie Zhu ◽  
Xun Sun ◽  
Li-Fan Zhang ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Therapeutic Potential ◽  
Amyloid Β ◽  
Synaptic Proteins ◽  
Morris Water Maze Test ◽  
Phosphorylated Tau ◽  
Tau Pathology ◽  
Maze Test ◽  
N2a Cells ◽  
Tau Aggregation

Background: Alzheimer’s Disease (AD) is characterized by the presence of extracellular amyloid-β (Aβ) plaques and intraneuronal neurofibrillary tangles assembled by the microtubuleassociated protein tau. Increasing evidence demonstrated that tau pathology played an important role in AD progression. Resveratrol (RSV) has previously proved to exert neuroprotective effect against AD by inhibiting Aβ generation and Aβ-induced neurocytotoxicity, while its effect on tau pathology is still unknown. Method: The effect of RSV on tau aggregation was measured by Thioflavin T fluorescence and Transmission electron microscope imaging. The effect of RSV on tau oligomer-induced cytotoxicity was assessed by MTT assay and the uptake of extracellular tau by N2a cells was determined by immunocytochemistry. 6-month-old male PS19 mice were treated with RSV or vehicle by oral administration (gavage) once a day for 5 weeks. The cognitive performance was determined using Morris water maze test, object recognition test and Y-maze test. The levels of phosphorylated-tau, gliosis, proinflammatory cytokines such as TNF-α and IL-1β, and synaptic proteins including synaptophysin and PSD95 in the brains of the mice were evaluated by immunoblotting, immunostaining and ELISA, respectively. Results: RSV significantly inhibited tau aggregation and tau oligomer-induced cytotoxicity, and blocked the uptake of extracellular tau oligomers by N2a cells. When applied to PS19 mice, RSV treatment effectively rescued cognitive deficits, reducing the levels of phosphorylated tau, neuroinflammation and synapse loss in the brains of mice. Conclusion: These findings suggest that RSV has promising therapeutic potential for AD and other tauopathies.

scholarly journals Development of the Cerebrospinal Fluid in Early Stage after Hemorrhage in the Central Nervous System

Life ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 300
Author(s):  
Petr Kelbich ◽  
Aleš Hejčl ◽  
Jan Krejsek ◽  
Tomáš Radovnický ◽  
Inka Matuchová ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Early Stage ◽  
Rank Test ◽  
Signed Rank ◽  
Signed Rank Test ◽  
The Central Nervous System ◽  
Poor Outcomes ◽  
Molecular Patterns

Extravasation of blood in the central nervous system (CNS) represents a very strong damaged associated molecular patterns (DAMP) which is followed by rapid inflammation and can participate in worse outcome of patients. We analyzed cerebrospinal fluid (CSF) from 139 patients after the CNS hemorrhage. We compared 109 survivors (Glasgow Outcome Score (GOS) 5-3) and 30 patients with poor outcomes (GOS 2-1). Statistical evaluations were performed using the Wilcoxon signed-rank test and the Mann–Whitney U test. Almost the same numbers of erythrocytes in both subgroups appeared in days 0–3 (p = 0.927) and a significant increase in patients with GOS 2-1 in days 7–10 after the hemorrhage (p = 0.004) revealed persistence of extravascular blood in the CNS as an adverse factor. We assess 43.3% of patients with GOS 2-1 and only 27.5% of patients with GOS 5-3 with low values of the coefficient of energy balance (KEB < 15.0) in days 0–3 after the hemorrhage as a trend to immediate intensive inflammation in the CNS of patients with poor outcomes. We consider significantly higher concentration of total protein of patients with GOS 2-1 in days 0–3 after hemorrhage (p = 0.008) as the evidence of immediate simultaneously manifested intensive inflammation, swelling of the brain and elevation of intracranial pressure.

In silico analysis of selenoprotein N (Gallus gallus): absence of EF-hand motif and the role of CUGS-helix domain in antioxidant protection

Metallomics ◽  
2021 ◽  
Vol 13 (3) ◽  
Author(s):  
Shi-Yong Zhu ◽  
Li-Li Liu ◽  
Yue-Qiang Huang ◽  
Xiao-Wei Li ◽  
Milton Talukder ◽  
...  
Keyword(s):  
In Silico ◽  
Common Ancestor ◽  
In Silico Analysis ◽  
Antioxidant Protection ◽  
Jnk Pathway ◽  
Downstream Target ◽  
Ef Hand ◽  
Silico Analysis

Abstract Selenoprotein N (SEPN1) is critical to the normal muscular physiology. Mutation of SEPN1 can raise congenital muscular disorder in human. It is also central to maturation and structure of skeletal muscle in chicken. However, human SEPN1 contained an EF-hand motif, which was not found in chicken. And the biochemical and molecular characterization of chicken SEPN1 remains unclear. Hence, protein domains, transcription factors, and interactions of Ca2+ in SEPN1 were analyzed in silico to provide the divergence and homology between chicken and human in this work. The results showed that vertebrates’ SEPN1 evolved from a common ancestor. Human and chicken's SEPN1 shared a conserved CUGS-helix domain with function in antioxidant protection. SEPN1 might be a downstream target of JNK pathway, and it could respond to multiple stresses. Human's SEPN1 might not combine with Ca2+ with a single EF-hand motif in calcium homeostasis, and chicken SEPN1 did not have the EF-hand motif in the prediction, indicating the EF-hand motif malfunctioned in chicken SEPN1.

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