scholarly journals Molecular Targets in Alzheimer’s Disease: From Pathogenesis to Therapeutics

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Xuan Cheng ◽  
Lu Zhang ◽  
Ya-Jun Lian
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signaling Pathways ◽  
Therapeutic Strategy ◽  
Tea Polyphenols ◽  
Pharmacological Targets ◽  
Drug Designing ◽  
Multiple Health ◽  
Insight Into ◽  
Cell Signaling Pathways

Alzheimer’s disease(AD) is characterized by progressive cognitive decline usually beginning with impairment in the ability to form recent memories. Nonavailability of definitive therapeutic strategy urges developing pharmacological targets based on cell signaling pathways. A great revival of interest in nutraceuticals and adjuvant therapy has been put forward. Tea polyphenols for their multiple health benefits have also attracted the attention of researchers. Tea catechins showed enough potentiality to be used in future as therapeutic targets to provide neuroprotection against AD. This review attempts to present a concise map of different receptor signaling pathways associated with AD with an insight into drug designing based on the proposed signaling pathways, molecular mechanistic details of AD pathogenesis, and a scientific rationale for using tea polyphenols as proposed therapeutic agents in AD.

scholarly journals Are signaling pathways inversely regulated in Alzheimer's disease and glioblastoma multiforme?

2018 ◽  
Vol 1 (1) ◽  
Author(s):  
William G. O'Neal ◽  
Debomoy K. Lahiri, Ph.D ◽  
Mahua Dey, M.D ◽  
Ruizhi Wang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glioblastoma Multiforme ◽  
Cell Signaling ◽  
Signaling Pathways ◽  
Synaptic Proteins ◽  
Low Grade ◽  
Inverse Association ◽  
Potential Impact ◽  
Cell Signaling Pathways

Background: Epidemiological studies suggest an inverse association between cancer and neurodegenerative disorders, including Alzheimer’s disease (AD). AD and cancers, such as glioblastoma multiforme (GBM), are characterized by abnormal but opposing cellular behavior. AD is characterized by accumulation of the processing products of amyloid β (Aβ) and its metabolizing enzymes amyloid precursor protein (APP), β-secretase (or BACE1), and γ-secretase. Our rationale is unraveling cell signaling pathways linking AD and GBM. We hypothesized low-grade gliomas (LGG) and high-grade gliomas (HGG) would have differential expression of neuronal and synaptic markers. Furthermore, protein expression profiles of these markers, APP metabolites, and BACE1 would be different among LGG, HGG, and AD cases.  Experimental Design or project methods: Specific neuronal protein markers (e.g., NSE), presynaptic proteins (e.g., synaptophysin and SNAP25), and post-synaptic proteins (e.g., PSD-95) have been measured in glioma samples. Characterization are done by Western immunoblotting and ELISA. Protein biomarkers will be analyzed in LGG and HGG of biopsy samples, and the results will be compared with brain samples from AD cases.  Results: Using specific primary and secondary antibodies and optimal protein range, we have standardized an immunoblotting procedure to detect our desired proteins in blinded LGG and HGG samples. After unblinding and analyzing results, expression signals will be compared between GBM and AD brain samples.  Conclusion and potential impact: Our results would shed light on diverging and/or shared cell signaling pathways between AD and GBM. In addition, potential impact would be utilizing GBM-derived cultures to test and develop therapeutics for both AD and GBM.

scholarly journals Delta-secretase cleavage of Tau mediates its pathology and propagation in Alzheimer’s disease

2020 ◽  
Vol 52 (8) ◽  
pp. 1275-1287
Author(s):  
Seong Su Kang ◽  
Eun Hee Ahn ◽  
Keqiang Ye
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Strategy ◽  
Senile Plaques ◽  
Tau Pathology ◽  
Disease Modifying ◽  
Tau Aggregation ◽  
The Brain ◽  
Insight Into

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disease with age as a major risk factor. AD is the most common dementia with abnormal structures, including extracellular senile plaques and intraneuronal neurofibrillary tangles, as key neuropathologic hallmarks. The early feature of AD pathology is degeneration of the locus coeruleus (LC), which is the main source of norepinephrine (NE) supplying various cortical and subcortical areas that are affected in AD. The spread of Tau deposits is first initiated in the LC and is transported in a stepwise manner from the entorhinal cortex to the hippocampus and then to associative regions of the neocortex as the disease progresses. Most recently, we reported that the NE metabolite DOPEGAL activates delta-secretase (AEP, asparagine endopeptidase) and triggers pathological Tau aggregation in the LC, providing molecular insight into why LC neurons are selectively vulnerable to developing early Tau pathology and degenerating later in the disease and how δ-secretase mediates the spread of Tau pathology to the rest of the brain. This review summarizes our current understanding of the crucial role of δ-secretase in driving and spreading AD pathologies by cleaving multiple critical players, including APP and Tau, supporting that blockade of δ-secretase may provide an innovative disease-modifying therapeutic strategy for treating AD.

scholarly journals An Insight into the Molecular and Therapeutic Targets of Amyloid Plaques in Alzheimer's Disease and an Update on the Prospects of Drugs in Research

2021 ◽  
pp. 1-51
Author(s):  
Jaya Thomas ◽  
◽  
Samson Wilson ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Symptomatic Relief ◽  
Amyloid Plaque ◽  
The Past ◽  
Pharmacological Targets ◽  
Drug Treatments ◽  
Global Concern ◽  
Potential Area ◽  
Insight Into

Alzheimer’s disease (AD) is characterized by progressive loss of cognition and a gradual decrease in memory. Though AD is considered the most persistent form of dementia and a global concern, no complete cure or agents that can completely halt the progression of AD have been found. In the past years, considerable advancements in the understanding of cellular and molecular changes associated with AD has been investigated and numerous pharmacological targets have been recognized to enable drug development for the condition. Amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFT) are the major attributes of AD. Symptomatic relief is the only possible treatment available at present and a disease modifying drug is of utmost importance. Development of drugs that can inhibit different targets responsible for the formation of plaques is a potential area in AD research. This review is not a complete list of all possible targets for AD but serves to highlight the targets related to amyloid pathology and pathway concerned with the formation of amyloid fragments. This shall serve as a prospect in identification of amyloid plaque inhibitors and pave the strategies for newer drug treatments. Nevertheless, substantial research is done in this area but to bridle, the clinical difficulty remains a concern.

Voxel-based morphometry (VBM) analysis in Alzheimer's disease an insight into heterogeneity of cerebral atrophy

2005 ◽  
Vol 25 (1_suppl) ◽  
pp. S338-S338
Author(s):  
Akihiko Shiino ◽  
Toshiyuki Watanabe ◽  
Ichiro Akiguchi ◽  
Shigehiro Morikawa ◽  
Toshiro Inubushi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebral Atrophy ◽  
Voxel Based Morphometry ◽  
Insight Into

The Role of Lipids and Membranes in the Pathogenesis of Alzheimer's Disease: A Comprehensive View

2018 ◽  
Vol 15 (13) ◽  
pp. 1191-1212 ◽  
Author(s):  
Botond Penke ◽  
Gábor Paragi ◽  
János Gera ◽  
Róbert Berkecz ◽  
Zsolt Kovács ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signaling Pathways ◽  
Membrane Lipids ◽  
Specific Protein ◽  
Dietary Factors ◽  
Lipid Signaling ◽  
Special Role ◽  
Aβ Peptides

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.

scholarly journals Continuous and Cyclic Progesterone Differentially Interact with Estradiol in the Regulation of Alzheimer-Like Pathology in Female 3×Transgenic-Alzheimer’s Disease Mice

Endocrinology ◽  
2010 ◽  
Vol 151 (6) ◽  
pp. 2713-2722 ◽  
Author(s):  
Jenna C. Carroll ◽  
Emily R. Rosario ◽  
Angela Villamagna ◽  
Christian J. Pike
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Postmenopausal Women ◽  
Transgenic Mouse Model ◽  
Dependent Behavior ◽  
Potential Efficacy ◽  
Increased Risk ◽  
Neural Interactions ◽  
Β Amyloid ◽  
Insight Into

Depletion of estrogens and progesterone at menopause has been linked to an increased risk for the development of Alzheimer’s disease (AD) in women. A currently controversial literature indicates that although treatment of postmenopausal women with hormone therapy (HT) may reduce the risk of AD, several parameters of HT may limit its potential efficacy and perhaps, even exacerbate AD risk. One such parameter is continuous vs. cyclic delivery of the progestogen component of HT. Recent experimental evidence suggests that continuous progesterone can attenuate neural actions of estradiol (E2). In the present study, we compared the effects of continuous and cyclic progesterone treatment in the presence and absence of E2 in ovariectomized 3×Tg-AD mice, a transgenic mouse model of AD. We found that ovariectomy-induced hormone depletion increases AD-like pathology in female 3×Tg-AD mice, including accumulation of β-amyloid, tau hyperphosphorylation, and impaired hippocampal-dependent behavior. E2 treatment alone prevents the increases in pathology. Continuous progesterone did not affect β-amyloid levels when delivered alone but blocked the Aβ-lowering action of E2. In contrast, cyclic progesterone significantly reduced β-amyloid levels by itself and enhanced rather than inhibited the E2 effects. These results provide new insight into the neural interactions between E2 and progesterone that may prove valuable in optimizing HT regimens in postmenopausal women.

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

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.

scholarly journals Peptides Derived from Growth Factors to Treat Alzheimer’s Disease

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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