scholarly journals Sodium rutin ameliorates Alzheimer’s disease–like pathology by enhancing microglial amyloid-β clearance

2019 ◽  
Vol 5 (2) ◽  
pp. eaau6328 ◽  
Author(s):  
Rui-Yuan Pan ◽  
Jun Ma ◽  
Xiang-Xi Kong ◽  
Xiao-Feng Wang ◽  
Shuo-Shuo Li ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Spatial Learning And Memory ◽  
Metabolic Switch ◽  
Sufficient Energy ◽  
Aβ Clearance ◽  
The Brain

The accumulation of aggregated amyloid-β (Aβ) in the brain is the first critical step in the pathogenesis of Alzheimer’s disease (AD), which also includes synaptic impairment, neuroinflammation, neuronal loss, and eventual cognitive defects. Emerging evidence suggests that impairment of Aβ phagocytosis and clearance is a common phenotype in late-onset AD. Rutin (quercetin-3-rutinoside) has long been investigated as a natural flavonoid with different biological functions in some pathological circumstances. Sodium rutin (NaR), could promote Aβ clearance by increasing microglial by increasing the expression levels of phagocytosis-related receptors in microglia. Moreover, NaR promotes a metabolic switch from anaerobic glycolysis to mitochondrial OXPHOS (oxidative phosphorylation), which could provide microglia with sufficient energy (ATP) for Aβ clearance. Thus, NaR administration could attenuate neuroinflammation and enhance mitochondrial OXPHOS and microglia-mediated Aβ clearance, ameliorating synaptic plasticity impairment and eventually reversing spatial learning and memory deficits. Our findings suggest that NaR is a potential therapeutic agent for AD.

scholarly journals Neuronal heparan sulfates promote amyloid pathology by modulating brain amyloid-β clearance and aggregation in Alzheimer’s disease

2016 ◽  
Vol 8 (332) ◽  
pp. 332ra44-332ra44 ◽  
Author(s):  
Chia-Chen Liu ◽  
Na Zhao ◽  
Yu Yamaguchi ◽  
John R. Cirrito ◽  
Takahisa Kanekiyo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Therapeutic Interventions ◽  
Postmortem Human Brain ◽  
Aβ Clearance ◽  
Heparan Sulfates ◽  
The Brain

Accumulation of amyloid-β (Aβ) peptide in the brain is the first critical step in the pathogenesis of Alzheimer’s disease (AD). Studies in humans suggest that Aβ clearance from the brain is frequently impaired in late-onset AD. Aβ accumulation leads to the formation of Aβ aggregates, which injure synapses and contribute to eventual neurodegeneration. Cell surface heparan sulfates (HSs), expressed on all cell types including neurons, have been implicated in several features in the pathogenesis of AD including its colocalization with amyloid plaques and modulatory role in Aβ aggregation. We show that removal of neuronal HS by conditional deletion of the Ext1 gene, which encodes an essential glycosyltransferase for HS biosynthesis, in postnatal neurons of amyloid model APP/PS1 mice led to a reduction in both Aβ oligomerization and the deposition of amyloid plaques. In vivo microdialysis experiments also detected an accelerated rate of Aβ clearance in the brain interstitial fluid, suggesting that neuronal HS either inhibited or represented an inefficient pathway for Aβ clearance. We found that the amounts of various HS proteoglycans (HSPGs) were increased in postmortem human brain tissues from AD patients, suggesting that this pathway may contribute directly to amyloid pathogenesis. Our findings have implications for AD pathogenesis and provide insight into therapeutic interventions targeting Aβ-HSPG interactions.

scholarly journals GPCR19 regulates P2X7R-mediated NLRP3 inflammasomal activation of microglia by Amyloid β in Alzheimer’s diseases

2020 ◽  
Author(s):  
Jahirul Islam ◽  
Jung-Ah Cho ◽  
Ju-yong Kim ◽  
Kyung-Sun Park ◽  
Young-Jae koh ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nlrp3 Inflammasome ◽  
Memory Function ◽  
Scavenger Receptor ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Priming Phase ◽  
5Xfad Mice ◽  
The Brain

Abstract Amyloid β (Aβ) and/or ATP activates NLRP3 inflammasome (N3I) by P2 × 7R ion channel of microglia, which is crucial in neuroinflammation shown in Alzheimer’s disease (AD). Due to polymorphisms, subtypes, and ubiquitous expression of P2 × 7R, inhibition of P2 × 7R has not been effective for AD. We first report that GPCR19 is a prerequisite for P2 × 7R-mediated N3I activation and Taurodeoxycholate (TDCA), a GPCR19 ligand, inhibited the priming phase of N3I activation, suppressed P2 × 7R expression and P2 × 7R-mediated Ca++ mobilization, and N3I oligomerization which is essential for production of IL-1β/IL-18. Further, TDCA increased expression of scavenger receptor (SR) A, enhanced phagocytosis of Aβ, and decreased Aβ plaque numbers in the brain of 5x Familial Alzheimer’s disease (5xFAD) mice. TDCA also reduced microgliosis, prevented neuronal loss, and improved memory function of 5xFAD mice. The pleiotropic roles of GPCR19 in P2 × 7-mediated N3I activation suggest that targeting GPCR19 might resolve neuroinflammation in AD patients.

scholarly journals A Study of the SORL1 Gene in the Pathogenesis of Late-onset Alzheimer’s Disease by Affecting the Expression of BDNF

2021 ◽  
Author(s):  
Mingri Zhao ◽  
Jiangfeng Liu ◽  
Jingli He ◽  
Xun Chen ◽  
Yanjin Feng ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Cell Model ◽  
Amyloid Β ◽  
Cognitive Disorders ◽  
Amyloid Β Protein ◽  
Bdnf Expression ◽  
The Brain

Abstract BackgroundAlzheimer’s disease is a neurodegenerative disease characterized by progressive memory impairment and other cognitive disorders. It is divided into Familial Alzheimer's disease (FAD) and Sporadic Alzheimer's disease (SAD). SAD is also called delayed Late-onset Alzheimer's disease (LOAD). Sortilin Related Receptor 1 (SORL1) is a high-risk pathogenic gene of LOAD, which can participate in the occurrence and development of AD by affecting the transport and metabolism of intracellular β-amyloid precursor protein (APP). The expression of SORL1 is significantly downregulated in patients with LOAD.ResultsIn the SORL1 knockout (SORL1 KO) mouse model constructed by CRISPR/cas9, we found that the expression of Brain Derived Neurotrophic Factor (BDNF) in the brain of SORL1 KO mice was significantly down-regulated and Amyloid β-protein (Aβ) deposition was found in the brain ofSORL1 KO mice. Through the SORL1 knockdown N2a cell model constructed by shRNA, we also found that when the SORL1 expression was knocked down, the BDNF expression was also downregulated and the cell viability decreased. The results of immunohistochemistry and in vitro cell model experiments suggest that the downregulation of BDNF caused by SORL1 knockdown may be mainly achieved by affecting the expression and distribution of N-Methyl-D-aspartate (NMDAR).ConclusionsSORL1 knockout changes the expression and distribution of NMDAR in cells, downregulates the expression of BDNF, and thus affects the learning and memory of mice.

scholarly journals Heparanase overexpression impedes perivascular clearance of amyloid-β from murine brain: relevance to Alzheimer’s disease

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Xiao Zhang ◽  
Paul O’Callaghan ◽  
Honglian Li ◽  
Yingxia Tan ◽  
Ganlin Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Multiple Roles ◽  
Amyloid Angiopathy ◽  
Elevated Expression ◽  
Aβ Clearance ◽  
The Brain ◽  
Perivascular Drainage ◽  
Astrocyte Endfeet

AbstractDefective amyloid-β (Aβ) clearance from the brain is a major contributing factor to the pathophysiology of Alzheimer’s disease (AD). Aβ clearance is mediated by macrophages, enzymatic degradation, perivascular drainage along the vascular basement membrane (VBM) and transcytosis across the blood–brain barrier (BBB). AD pathology is typically associated with cerebral amyloid angiopathy due to perivascular accumulation of Aβ. Heparan sulfate (HS) is an important component of the VBM, thought to fulfill multiple roles in AD pathology. We previously showed that macrophage-mediated clearance of intracortically injected Aβ was impaired in the brains of transgenic mice overexpressing heparanase (Hpa-tg). This study revealed that perivascular drainage was impeded in the Hpa-tg brain, evidenced by perivascular accumulation of the injected Aβ in the thalamus of Hpa-tg mice. Furthermore, endogenous Aβ accumulated at the perivasculature of Hpa-tg thalamus, but not in control thalamus. This perivascular clearance defect was confirmed following intracortical injection of dextran that was largely retained in the perivasculature of Hpa-tg brains, compared to control brains. Hpa-tg brains presented with thicker VBMs and swollen perivascular astrocyte endfeet, as well as elevated expression of the BBB-associated water-pump protein aquaporin 4 (AQP4). Elevated levels of both heparanase and AQP4 were also detected in human AD brain. These findings indicate that elevated heparanase levels alter the organization and composition of the BBB, likely through increased fragmentation of BBB-associated HS, resulting in defective perivascular drainage. This defect contributes to perivascular accumulation of Aβ in the Hpa-tg brain, highlighting a potential role for heparanase in the pathogenesis of AD.

scholarly journals Night Photostimulation of Clearance of Beta-Amyloid from Mouse Brain: New Strategies in Preventing Alzheimer’s Disease

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3289
Author(s):  
Oxana Semyachkina-Glushkovskaya ◽  
Thomas Penzel ◽  
Inna Blokhina ◽  
Alexander Khorovodov ◽  
Ivan Fedosov ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Elderly Age ◽  
Clearing Functions ◽  
Aβ Clearance ◽  
The Brain ◽  
Ad Therapy ◽  
New Strategies ◽  
Stimulation Of

The deposition of amyloid-β (Aβ) in the brain is a risk factor for Alzheimer’s disease (AD). Therefore, new strategies for the stimulation of Aβ clearance from the brain can be useful in preventing AD. Transcranial photostimulation (PS) is considered a promising method for AD therapy. In our previous studies, we clearly demonstrated the PS-mediated stimulation of lymphatic clearing functions, including Aβ removal from the brain. There is increasing evidence that sleep plays an important role in Aβ clearance. Here, we tested our hypothesis that PS at night can stimulate Aβ clearance from the brain more effectively than PS during the day. Our results on healthy mice show that Aβ clearance from the brain occurs faster at night than during wakefulness. The PS course at night improves memory and reduces Aβ accumulation in the brain of AD mice more effectively than the PS course during the day. Our results suggest that night PS is a more promising candidate as an effective method in preventing AD than daytime PS. These data are an important informative platform for the development of new noninvasive and nonpharmacological technologies for AD therapy as well as for preventing Aβ accumulation in the brain of people with disorder of Aβ metabolism, sleep deficit, elderly age, and jet lag.

Pharmacogenetics of Angiotensin-Converting Enzyme Inhibitors in Patients with Alzheimer's Disease Dementia

2018 ◽  
Vol 15 (4) ◽  
pp. 386-398 ◽  
Author(s):  
Fabricio Ferreira de Oliveira ◽  
Elizabeth Suchi Chen ◽  
Marilia Cardoso Smith ◽  
Paulo Henrique Ferreira Bertolucci
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Angiotensin Converting Enzyme ◽  
Cognitive Decline ◽  
Enzyme Inhibitors ◽  
Late Onset ◽  
Amyloid Β ◽  
Converting Enzyme ◽  
Converting Enzyme Inhibitors ◽  
Alzheimer’S Disease Dementia

Background: While the angiotensin-converting enzyme degrades amyloid-β, angiotensinconverting enzyme inhibitors (ACEis) may slow cognitive decline by way of cholinergic effects, by increasing brain substance P and boosting the activity of neprilysin, and by modulating glucose homeostasis and augmenting the secretion of adipokines to enhance insulin sensitivity in patients with Alzheimer’s disease dementia (AD). We aimed to investigate whether ACE gene polymorphisms rs1800764 and rs4291 are associated with cognitive and functional change in patients with AD, while also taking APOE haplotypes and anti-hypertensive treatment with ACEis into account for stratification. Methods: Consecutive late-onset AD patients were screened with cognitive tests, while their caregivers were queried for functional and caregiver burden scores. Prospective pharmacogenetic correlations were estimated for one year, considering APOE and ACE genotypes and haplotypes, and treatment with ACEis. Results: For 193 patients, minor allele frequencies were 0.497 for rs1800764 – C (44.6% heterozygotes) and 0.345 for rs4291 – T (38.9% heterozygotes), both in Hardy-Weinberg equilibrium. Almost 94% of all patients used cholinesterase inhibitors, while 155 (80.3%) had arterial hypertension, and 124 used ACEis. No functional impacts were found regarding any genotypes or pharmacological treatment. Either for carriers of ACE haplotypes that included rs1800764 – T and rs4291 – A, or for APOE4- carriers of rs1800764 – T or rs4291 – T, ACEis slowed cognitive decline independently of blood pressure variations. APOE4+ carriers were not responsive to treatment with ACEis. Conclusion: ACEis may slow cognitive decline for patients with AD, more remarkably for APOE4- carriers of specific ACE genotypes.

scholarly journals Tau and TDP-43 synergy: a novel therapeutic target for sporadic late-onset Alzheimer’s disease

GeroScience ◽  
2021 ◽  
Author(s):  
Caitlin S. Latimer ◽  
Nicole F. Liachko
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Hippocampal Sclerosis ◽  
Model Organism ◽  
Amyloid Β ◽  
Underlying Disease ◽  
Therapeutic Interventions ◽  
Disease Biology ◽  
Rapid Cognitive Decline

AbstractAlzheimer’s disease (AD) is traditionally defined by the presence of two types of protein aggregates in the brain: amyloid plaques comprised of the protein amyloid-β (Aβ) and neurofibrillary tangles containing the protein tau. However, a large proportion (up to 57%) of AD patients also have TDP-43 aggregates present as an additional comorbid pathology. The presence of TDP-43 aggregates in AD correlates with hippocampal sclerosis, worse brain atrophy, more severe cognitive impairment, and more rapid cognitive decline. In patients with mixed Aβ, tau, and TDP-43 pathology, TDP-43 may interact with neurodegenerative processes in AD, worsening outcomes. While considerable progress has been made to characterize TDP-43 pathology in AD and late-onset dementia, there remains a critical need for mechanistic studies to understand underlying disease biology and develop therapeutic interventions. This perspectives article reviews the current understanding of these processes from autopsy cohort studies and model organism-based research, and proposes targeting neurotoxic synergies between tau and TDP-43 as a new therapeutic strategy for AD with comorbid TDP-43 pathology.

scholarly journals Oral Amylin Treatment Reduces the Pathological Cascade of Alzheimer’s Disease in a Mouse Model

2021 ◽  
Vol 36 ◽  
pp. 153331752110128
Author(s):  
Hana Na ◽  
Hua Tian ◽  
Zhengrong Zhang ◽  
Qiang Li ◽  
Jack B. Yang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Calcium Binding ◽  
Oral Delivery ◽  
Amyloid Β ◽  
Enteric Neurons ◽  
Cyclin Dependent Kinase ◽  
Receptor Activity Modifying Proteins ◽  
The Brain ◽  
Cyclin Dependent Kinase 5

Intraperitoneal injection of amylin or its analog reduces Alzheimer’s disease (AD) pathology in the brains. However, self-injecting amylin analogs is difficult for patients due to cognitive deficits. This work aims to study the effects of amylin on the brain could be achieved by oral delivery as some study reported that amylin receptor may be present in the gastrointestinal tract. A 6-week course of oral amylin treatment reduced components of AD pathology, including the levels of amyloid-β, phosphorylated tau, and ionized calcium binding adaptor molecule 1. The treatment reduced active forms of cyclin-dependent kinase 5. Oral amylin treatment led to improvements in social deficit in AD mouse. Using immunofluorescence, we observed the amylin receptor complexed with the calcitonin receptor and receptor activity-modifying proteins in the enteric neurons. The study suggests the potential of the oral delivery of amylin analogs for the treatment of AD and other neurodegenerative diseases through enteric neurons.

scholarly journals Identification of Novel Cathepsin B Inhibitors with Implications in Alzheimer’s Disease: Computational Refining and Biochemical Evaluation

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1946
Author(s):  
Nitin Chitranshi ◽  
Ashutosh Kumar ◽  
Samran Sheriff ◽  
Veer Gupta ◽  
Angela Godinez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hydrogen Bond ◽  
Virtual Screening ◽  
Cathepsin B ◽  
Amyloid Β ◽  
Proteolytic Degradation ◽  
Hydrogen Bond Acceptor ◽  
Starting Point ◽  
The Brain

Amyloid precursor protein (APP), upon proteolytic degradation, forms aggregates of amyloid β (Aβ) and plaques in the brain, which are pathological hallmarks of Alzheimer’s disease (AD). Cathepsin B is a cysteine protease enzyme that catalyzes the proteolytic degradation of APP in the brain. Thus, cathepsin B inhibition is a crucial therapeutic aspect for the discovery of new anti-Alzheimer’s drugs. In this study, we have employed mixed-feature ligand-based virtual screening (LBVS) by integrating pharmacophore mapping, docking, and molecular dynamics to detect small, potent molecules that act as cathepsin B inhibitors. The LBVS model was generated by using hydrophobic (HY), hydrogen bond acceptor (HBA), and hydrogen bond donor (HBD) features, using a dataset of 24 known cathepsin B inhibitors of both natural and synthetic origins. A validated eight-feature pharmacophore hypothesis (Hypo III) was utilized to screen the Maybridge chemical database. The docking score, MM-PBSA, and MM-GBSA methodology was applied to prioritize the lead compounds as virtual screening hits. These compounds share a common amide scaffold, and showed important interactions with Gln23, Cys29, His110, His111, Glu122, His199, and Trp221. The identified inhibitors were further evaluated for cathepsin-B-inhibitory activity. Our study suggests that pyridine, acetamide, and benzohydrazide compounds could be used as a starting point for the development of novel therapeutics.

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