Signaling pathways and posttranslational modifications of tau in Alzheimer's disease: the humanization of yeast cells

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.

Download Full-text

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.

Download Full-text

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.

Download Full-text

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.

Download Full-text

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

Download Full-text

Stabilization of dynamic microtubules by mDia1 drives Tau-dependent Aβ1–42 synaptotoxicity

The Journal of Cell Biology ◽

10.1083/jcb.201701045 ◽

2017 ◽

Vol 216 (10) ◽

pp. 3161-3178 ◽

Cited By ~ 20

Author(s):

Xiaoyi Qu ◽

Feng Ning Yuan ◽

Carlo Corona ◽

Silvia Pasini ◽

Maria Elena Pero ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Axonal Transport ◽

Dendritic Spines ◽

Posttranslational Modifications ◽

Hippocampal Neurons ◽

Neuronal Damage ◽

Driving Factors ◽

Hyperphosphorylated Tau ◽

Tau Hyperphosphorylation

Oligomeric Amyloid β1–42 (Aβ) plays a crucial synaptotoxic role in Alzheimer’s disease, and hyperphosphorylated tau facilitates Aβ toxicity. The link between Aβ and tau, however, remains controversial. In this study, we find that in hippocampal neurons, Aβ acutely induces tubulin posttranslational modifications (PTMs) and stabilizes dynamic microtubules (MTs) by reducing their catastrophe frequency. Silencing or acute inhibition of the formin mDia1 suppresses these activities and corrects the synaptotoxicity and deficits of axonal transport induced by Aβ. We explored the mechanism of rescue and found that stabilization of dynamic MTs promotes tau-dependent loss of dendritic spines and tau hyperphosphorylation. Collectively, these results uncover a novel role for mDia1 in Aβ-mediated synaptotoxicity and demonstrate that inhibition of MT dynamics and accumulation of PTMs are driving factors for the induction of tau-mediated neuronal damage.

Download Full-text

Loss of miR-369 Promotes Tau Phosphorylation by Targeting the Fyn and Serine/Threonine-Protein Kinase 2 Signaling Pathways in Alzheimer’s Disease Mice

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2019.00365 ◽

2020 ◽

Vol 11 ◽

Cited By ~ 2

Author(s):

Xiaoguang Yao ◽

Xiaohui Xian ◽

Mingxing Fang ◽

Shujuan Fan ◽

Wenbin Li

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Protein Kinase ◽

Signaling Pathways ◽

Tau Phosphorylation

Download Full-text

Impaired apoptosis in lymphoblasts from Alzheimer’s disease patients: Cross-talk of Ca2+/calmodulin and ERK1/2 signaling pathways

Cellular and Molecular Life Sciences ◽

10.1007/s00018-007-7081-3 ◽

2007 ◽

Vol 64 (11) ◽

pp. 1437-1448 ◽

Cited By ~ 25

Author(s):

F. Bartolomé ◽

N. de las Cuevas ◽

Ú. Muñoz ◽

F. Bermejo ◽

Á. Martín-Requero

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Signaling Pathways ◽

Cross Talk

Download Full-text

Protein Homeostasis Networks and the Use of Yeast to Guide Interventions in Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21218014 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8014

Author(s):

Sudip Dhakal ◽

Ian Macreadie

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Stress Responses ◽

Cell Biology ◽

Neurodegenerative Disorder ◽

The Elderly ◽

Yeast Cells ◽

Yeast Genome ◽

Protein Homeostasis ◽

Age Related

Alzheimer’s Disease (AD) is a progressive multifactorial age-related neurodegenerative disorder that causes the majority of deaths due to dementia in the elderly. Although various risk factors have been found to be associated with AD progression, the cause of the disease is still unresolved. The loss of proteostasis is one of the major causes of AD: it is evident by aggregation of misfolded proteins, lipid homeostasis disruption, accumulation of autophagic vesicles, and oxidative damage during the disease progression. Different models have been developed to study AD, one of which is a yeast model. Yeasts are simple unicellular eukaryotic cells that have provided great insights into human cell biology. Various yeast models, including unmodified and genetically modified yeasts, have been established for studying AD and have provided significant amount of information on AD pathology and potential interventions. The conservation of various human biological processes, including signal transduction, energy metabolism, protein homeostasis, stress responses, oxidative phosphorylation, vesicle trafficking, apoptosis, endocytosis, and ageing, renders yeast a fascinating, powerful model for AD. In addition, the easy manipulation of the yeast genome and availability of methods to evaluate yeast cells rapidly in high throughput technological platforms strengthen the rationale of using yeast as a model. This review focuses on the description of the proteostasis network in yeast and its comparison with the human proteostasis network. It further elaborates on the AD-associated proteostasis failure and applications of the yeast proteostasis network to understand AD pathology and its potential to guide interventions against AD.

Download Full-text