Protective effects of hydroxy-α-sanshool from the pericarp of Zanthoxylum bungeanum Maxim. On D-galactose/AlCl3-induced Alzheimer's disease-like mice via Nrf2/HO-1 signaling pathways

Lipids participate in Amyloid Precursor Protein (APP) trafficking and processing - important factors in the initiation of Alzheimer’s disease (AD) pathogenesis and influence the formation of neurotoxic β-amyloid (Aβ) peptides. An important risk factor, the presence of ApoE4 protein in AD brain cells binds the lipids to AD. In addition, lipid signaling pathways have a crucial role in the cellular homeostasis and depend on specific protein-lipid interactions. The current review focuses on pathological alterations of membrane lipids (cholesterol, glycerophospholipids, sphingolipids) and lipid metabolism in AD and provides insight in the current understanding of biological membranes, their lipid structures and functions, as well as their role as potential therapeutic targets. Novel methods for studying the membrane structure and lipid composition will be reviewed in a broad sense whereas the use of lipid biomarkers for early diagnosis of AD will be shortly summarized. Interactions of Aβ peptides with the cell membrane and different subcellular organelles are reviewed. Next, the details of the most important lipid signaling pathways, including the role of the plasma membrane as stress sensor and its therapeutic applications are given. 4-hydroxy-2-nonenal may play a special role in the initiation of the pathogenesis of AD and thus the “calpain-cathepsin hypothesis” of AD is highlighted. Finally, the most important lipid dietary factors and their possible use and efficacy in the prevention of AD are discussed.

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Phosphoinositides signaling modulates microglial actin remodeling and phagocytosis in Alzheimer’s disease

Cell Communication and Signaling ◽

10.1186/s12964-021-00715-0 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Smita Eknath Desale ◽

Subashchandrabose Chinnathambi

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Signaling Pathways ◽

Amyloid Β ◽

Dietary Fatty Acids ◽

Receptor Expression ◽

Actin Binding ◽

Actin Remodeling ◽

Protein Deposits

AbstractAlzheimer’s disease is one of the neurodegenerative diseases, characterized by the accumulation of abnormal protein deposits, which disrupts signal transduction in neurons and other glia cells. The pathological protein in neurodegenerative diseases, Tau and amyloid-β contribute to the disrupted microglial signaling pathways, actin cytoskeleton, and cellular receptor expression. The important secondary messenger lipids i.e., phosphatidylinositols are largely affected by protein deposits of amyloid-β in Alzheimer’s disease. Phosphatidylinositols are the product of different phosphatidylinositol kinases and the state of phosphorylation at D3, D4, and D5 positions of inositol ring. Phosphatidylinositol 3,4,5-triphosphate (PI 3, 4, 5-P3) involves in phagocytic cup formation, cell polarization, whereas Phosphatidylinositol 4,5-bisphosphate (PI 4, 5-P2)-mediates the process of phagosomes formation and further its fusion with early endosome.. The necessary activation of actin-binding proteins such as Rac, WAVE complex, and ARP2/3 complex for the actin polymerization in the process of phagocytosis, migration is regulated and maintained by PI 3, 4, 5-P3 and PI 4, 5-P2. The ratio and types of fatty acid intake can influence the intracellular secondary lipid messengers along with the cellular content of phaphatidylcholine and phosphatidylethanolamine. The Amyloid-β deposits and extracellular Tau seeds disrupt phosphatidylinositides level and actin cytoskeletal network that hamper microglial-signaling pathways in AD. We hypothesize that being a lipid species intracellular levels of phosphatidylinositol would be regulated by dietary fatty acids. Further we are interested to understand phosphoinositide-based signaling cascades in phagocytosis and actin remodeling.

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Peptides Derived from Growth Factors to Treat Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22116071 ◽

2021 ◽

Vol 22 (11) ◽

pp. 6071

Author(s):

Suzanne Gascon ◽

Jessica Jann ◽

Chloé Langlois-Blais ◽

Mélanie Plourde ◽

Christine Lavoie ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Growth Factors ◽

Signaling Pathways ◽

Brain Structures ◽

Therapeutic Strategies ◽

Native Proteins ◽

Receptor Sites ◽

The Brain

Alzheimer’s disease (AD) is a devastating neurodegenerative disease characterized by progressive neuron losses in memory-related brain structures. The classical features of AD are a dysregulation of the cholinergic system, the accumulation of amyloid plaques, and neurofibrillary tangles. Unfortunately, current treatments are unable to cure or even delay the progression of the disease. Therefore, new therapeutic strategies have emerged, such as the exogenous administration of neurotrophic factors (e.g., NGF and BDNF) that are deficient or dysregulated in AD. However, their low capacity to cross the blood–brain barrier and their exorbitant cost currently limit their use. To overcome these limitations, short peptides mimicking the binding receptor sites of these growth factors have been developed. Such peptides can target selective signaling pathways involved in neuron survival, differentiation, and/or maintenance. This review focuses on growth factors and their derived peptides as potential treatment for AD. It describes (1) the physiological functions of growth factors in the brain, their neuronal signaling pathways, and alteration in AD; (2) the strategies to develop peptides derived from growth factor and their capacity to mimic the role of native proteins; and (3) new advancements and potential in using these molecules as therapeutic treatments for AD, as well as their limitations.

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The Associations of Plasma/Serum Carotenoids with Alzheimer’s Disease: A Systematic Review and Meta-Analysis

Journal of Alzheimer s Disease ◽

10.3233/jad-210384 ◽

2021 ◽

pp. 1-12

Author(s):

Mingyue Qu ◽

Hanxu Shi ◽

Kai Wang ◽

Xinggang Wang ◽

Nan Yu ◽

...

Keyword(s):

Systematic Review ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Meta Analysis ◽

Scoring Systems ◽

Serum Levels ◽

Epidemiological Studies ◽

Pooled Analysis ◽

Protective Effects ◽

Mean Differences

Background: Multiple lines of evidence indicate protective effects of carotenoids in Alzheimer’s disease (AD). However, previous epidemiological studies reported inconsistent results regarding the associations between carotenoids levels and the risk of AD. Objective: Our study aims to evaluate the associations of six major members of carotenoids with the occurrence of AD by conducting a systematic review and meta-analysis. Methods: Following PRISMA guidelines, a comprehensive literature search of PubMed, Web of Science, Ebsco, and PsycINFO databases was conducted, and the quality of each included studies was evaluated by a validated scoring systems. Standardized mean differences (SMD) with 95%confidence intervals (CI) were determined by using a random effects model. Heterogeneity was evaluated by I2 statistics. Publication bias was detected using funnel plots and Egger’s test. Results: Sixteen studies, with 10,633 participants were included. Pooled analysis showed significantly lower plasma/serum levels of lutein (SMD = –0.86, 95%CI: –1.67 to –0.05, p = 0.04) and zeaxanthin (SMD = –0.59; 95%CI: –1.12 to –0.06, p = 0.03) in patients with AD versus cognitively intact controls, while α-carotene (SMD = 0.21, 95%CI: –0.68 to 0.26, p = 0.39), β-carotene (SMD = 0.04, 95%CI: –0.57 to 0.65, p = 0.9), lycopene (SMD = –0.12, 95%CI: –0.96 to 0.72, p = 0.78), and β-cryptoxanthin (SMD = –0.09, 95%CI: –0.83 to 0.65, p = 0.81) did not achieve significant differences. Conclusion: Of six major members of carotenoids, only lutein and zeaxanthin concentrations in plasma/serum were inversely related to the risk of AD. More high-quality longitudinal studies are needed to verify these findings.

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Cytokine signaling convergence regulates the microglial state transition in Alzheimer’s disease

Cellular and Molecular Life Sciences ◽

10.1007/s00018-021-03810-0 ◽

2021 ◽

Author(s):

Shun-Fat Lau ◽

Amy K. Y. Fu ◽

Nancy Y. Ip

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Signaling Pathways ◽

State Transition ◽

Cytokine Signaling ◽

Interleukin 33 ◽

Beneficial Effects ◽

Activated State ◽

Therapeutic Development ◽

Functional States

AbstractGenetic analyses have revealed the pivotal contribution of microglial dysfunctions to the pathogenesis of Alzheimer’s disease (AD). Along AD progression, the accumulation of danger-associated molecular patterns (DAMPs) including beta-amyloid and hyperphosphorylated tau continuously stimulates microglia, which results in their chronic activation. Chronically activated microglia secrete excessive pro-inflammatory cytokines, which further regulate microglial responses towards DAMPs. This has spurred longstanding interest in targeting cytokine-induced microglial responses for AD therapeutic development. However, the cytokine-induced microglial state transition is not comprehensively understood. Cytokines are assumed to induce microglial state transition from a resting state to an activated state. However, recent evidence indicate that this microglial state transition involves multiple sequential functional states. Moreover, the mechanisms by which different functional states within the cytokine-induced microglial state transition regulate AD pathology remain unclear. In this review, we summarize how different cytokine signaling pathways, including those of IL-33 (interleukin-33), NLRP3 inflammasome–IL-1β, IL-10, and IL-12/IL-23, regulate microglial functions in AD. Furthermore, we discuss how the modulation of these cytokine signaling pathways can result in beneficial outcomes in AD. Finally, we describe a stepwise functional state transition of microglia induced by cytokine signaling that can provide insights into the molecular basis of the beneficial effects of cytokine modulation in AD and potentially aid therapeutic development.

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Microglia and its genetics in Alzheimer's Disease

Current Alzheimer Research ◽

10.2174/1567205018666211105140732 ◽

2021 ◽

Vol 18 ◽

Author(s):

Xinyan Liang ◽

Haijian Wu ◽

Mark Colt ◽

Xinying Guo ◽

Brock Pluimer ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Immune Cell ◽

Morphological Changes ◽

Association Studies ◽

Unmet Need ◽

Genome Wide Association Studies ◽

Protective Effects ◽

Risk Genes ◽

Main Component

: Alzheimer’s Disease (AD) is the most prevalent form of dementia across the world. While its discovery and pathological manifestations are centered on protein aggregations of amyloid-beta (Aβ) and hyperphosphorylated tau protein, neuroinflammation has emerged in the last decade as a main component of the disease in both pathogenesis and progression. As the main innate immune cell type in central nervous system (CNS), microglia play a very important role in regulating neuroinflammation, which occurs commonly in neurodegenerative conditions including AD. Under inflammatory response, microglia undergo morphological changes and status transition from homeostatic to activated forms. Different microglia subtypes displaying distinct genetic profiles have been identified in AD, and these signatures often link to AD risk genes identified from the genome-wide association studies (GWAS), such as APOE and TREM2. Furthermore, many of AD risk genes are highly enriched in microglia and specifically influence the functions of microglia in pathogenesis, e.g. releasing inflammatory cytokines and clearing Aβ. Therefore, building up a landscape of these risk genes in microglia, based on current preclinical studies and in the context of their pathogenic or protective effects, would largely help us to understand the complexed etiology of AD and provide new insight for the unmet need of effective treatment.

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Increased Cerebrospinal Fluid Production as a Possible Mechanism Underlying Caffeine's Protective Effect against Alzheimer's Disease

International Journal of Alzheimer s Disease ◽

10.4061/2011/617420 ◽

2011 ◽

Vol 2011 ◽

pp. 1-6 ◽

Cited By ~ 11

Author(s):

Peter Wostyn ◽

Debby Van Dam ◽

Kurt Audenaert ◽

Peter Paul De Deyn

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Late Onset ◽

Senile Plaques ◽

Protective Effects ◽

Caffeine Consumption ◽

Neuroprotective Effects ◽

Csf Production

Alzheimer's disease (AD), the most common type of dementia among older people, is characterized by the accumulation of β-amyloid (Aβ) senile plaques and neurofibrillary tangles composed of hyperphosphorylated tau in the brain. Despite major advances in understanding the molecular etiology of the disease, progress in the clinical treatment of AD patients has been extremely limited. Therefore, new and more effective therapeutic approaches are needed. Accumulating evidence from human and animal studies suggests that the long-term consumption of caffeine, the most commonly used psychoactive drug in the world, may be protective against AD. The mechanisms underlying the suggested beneficial effect of caffeine against AD remain to be elucidated. In recent studies, several potential neuroprotective effects of caffeine have been proposed. Interestingly, a recent study in rats showed that the long-term consumption of caffeine increased cerebrospinal fluid (CSF) production, associated with the increased expression of Na+-K+ATPase and increased cerebral blood flow. Compromised function of the choroid plexus and defective CSF production and turnover, with diminished clearance of Aβ, may be one mechanism implicated in the pathogenesis of late-onset AD. If reduced CSF turnover is a risk factor for AD, then therapeutic strategies to improve CSF flow are reasonable. In this paper, we hypothesize that long-term caffeine consumption could exert protective effects against AD at least in part by facilitating CSF production, turnover, and clearance. Further, we propose a preclinical experimental design allowing evaluation of this hypothesis.

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Brain Metabolomics Study on the Protective Effects of Ginsenosides Rg1 and Rb1 in an Alzheimer’s Disease Mouse Model

Pharmaceutical Analytical Chemistry Open Access ◽

10.4172/2471-2698.1000108 ◽

2015 ◽

Vol 01 (01) ◽

Author(s):

Naijing Li

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Protective Effects ◽

Metabolomics Study

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Disruption of Brain Cell Ion Homeostasis in Alzheimer's Disease by Oxy Radicals, and Signaling Pathways That Protect Therefrom

Chemical Research in Toxicology ◽

10.1021/tx9601317 ◽

1997 ◽

Vol 10 (5) ◽

pp. 507-517 ◽

Cited By ~ 32

Author(s):

Mark P. Mattson ◽

Robert J. Mark ◽

Katsutoshi Furukawa ◽

Annadora J. Bruce

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Signaling Pathways ◽

Ion Homeostasis ◽

Brain Cell

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Key Mechanisms and Potential Implications of Hericium erinaceus in NLRP3 Inflammasome Activation by Reactive Oxygen Species during Alzheimer’s Disease

Antioxidants ◽

10.3390/antiox10111664 ◽

2021 ◽

Vol 10 (11) ◽

pp. 1664

Author(s):

Marika Cordaro ◽

Angela Trovato Salinaro ◽

Rosalba Siracusa ◽

Ramona D’Amico ◽

Daniela Impellizzeri ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Nlrp3 Inflammasome ◽

Neuronal Degeneration ◽

Behavioral Changes ◽

Antioxidant Systems ◽

Inflammasome Activation ◽

Protective Effects ◽

Behavioral Alteration ◽

Hericium Erinaceus

Alzheimer’s disease (AD) is the principal cause of dementia, and its incidence increases with age. Altered antioxidant systems and inflammation have an important role in the etiology of neurodegenerative disorders. In this study, we evaluated the effects of Hericium erinaceus, a nutritional mushroom with important antioxidant effects, in a rat model of AD. Animals were injected with 70 mg/Kg of AlCl3 daily for 6 weeks, and Hericium erinaceus was administered daily by gavage. Before the experiment’s end date, behavioral test training was performed. At the end of the study, behavioral changes were assessed, and the animals were euthanized. Brain tissues were harvested for further analysis. AlCl3 mainly accumulates in the hippocampus, the principal region of the brain involved in memory functions and learning. Hericium erinaceus administration reduced behavioral changes and hippocampal neuronal degeneration. Additionally, it reduced phosphorylated Tau levels, aberrant APP overexpression, and β-amyloid accumulation. Moreover, Hericium erinaceus decreased the pro-oxidative and pro-inflammatory hippocampal alterations induced by AD. In particular, it reduced the activation of the NLRP3 inflammasome components, usually activated by increased oxidative stress during AD. Collectively, our results showed that Hericium erinaceus has protective effects on behavioral alteration and histological modification associated with AD due to the modulation of the oxidative and inflammatory pathways, as well as regulating cellular brain stress.

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