Alzheimer's Disease and Proteasome: The Therapeutic Development and Management

2018 ◽  
pp. 99-139
Author(s):  
Qunxing Ding ◽  
Haiyan Zhu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Development ◽  
Development And Management

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

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.

scholarly journals Traumatic Brain Injury Exacerbates Alzheimer's Disease Pathology in the Retinas of TgF344-AD Rats

2021 ◽  
Author(s):  
Conner Secora ◽  
Anne Vielle ◽  
Athena Ching-Jung Wang ◽  
Patricia Lenhart ◽  
Ernesto Salcedo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Transgenic Rat ◽  
Human Pathology ◽  
Innovative Model ◽  
Therapeutic Development ◽  
Post Impact ◽  
Transgenic Rat Model

Alzheimer's disease (AD) is a neurodegenerative condition that affects 6.2 million people age 65 and older in the U.S. alone, and is the leading cause of dementia. Moreover, AD can lead to visual impairment, and AD histopathology also manifests in the retina. However, the factors that modulate AD pathophysiology and lead to varied susceptibility and presentation in the population are not well understood. In this context, traumatic brain injury (TBI), which can arise from sport concussions, military combat, and other causes, is associated with a 2.3-fold higher risk of developing AD and AD-related dementias (ADRD). Thus, we set out to evaluate the effects of TBI, AD, and their combination, on retinal histopathology. Several animal models have been developed to investigate the mechanisms underlying AD, but many have been limited by imperfect recapitulation of human pathology, and no model of TBI-associated AD (AD-TBI) has been characterized. To address this gap, we generated an innovative model of AD-TBI by taking advantage of a transgenic rat model (Tg-F344-AD) shown to recapitulate the main features of human AD pathology, and combining it with a two-time unilateral controlled cortical impact paradigm to mimic repetitive mild TBI (rmTBI). Histopathological analyses at four months post-impact confirm the presence of AD markers in transgenic retinas, and an increased severity of AD pathology due to TBI. Together, these results contribute to our understanding of the effects of TBI on AD retinopathy, with implications for patient care and therapeutic development.

scholarly journals Genetic and Real-World Clinical Data, Combined with Empirical Validation, Nominate Jak-Stat Signaling as a Target for Alzheimer’s Disease Therapeutic Development

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 425 ◽  
Author(s):  
Alejo J. Nevado-Holgado ◽  
Elena Ribe ◽  
Laura Thei ◽  
Laura Furlong ◽  
Miguel-Angel Mayer ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Data ◽  
Real World ◽  
Association Studies ◽  
Rna Expression ◽  
Genome Wide Association Studies ◽  
Rodent Models ◽  
Therapeutic Development ◽  
Stat Pathway

As genome-wide association studies (GWAS) have grown in size, the number of genetic variants that have been associated per disease has correspondingly increased. Despite this increase in the number of single-nucleotide polymorphisms (SNPs) identified per disease, their biological interpretation has in many cases remained elusive. To address this, we have combined GWAS results with orthogonal sources of evidence, namely the current knowledge of molecular pathways; real-world clinical data from six million patients; RNA expression across tissues from Alzheimer’s disease (AD) patients, and purpose-built rodent models for experimental validation. In more detail, first we show that when examined at a pathway level, analysis of all GWAS studies groups AD in a cluster with disorders of immunity and inflammation. Using clinical data, we show that the degree of comorbidity of these diseases with AD correlates with the strength of their genetic association with molecular participants in the Janus kinases/signal transducer and activator of transcription (JAK-STAT) pathway. Using four independent RNA expression datasets we then find evidence for the altered regulation of JAK-STAT pathway genes in AD. Finally, we use both in vitro and in vivo rodent models to demonstrate that Aβ induces gene expression of the key drivers of this pathway, providing experimental evidence to validate these data-driven observations. These results therefore nominate JAK-STAT anomalies as a prominent aetiopathological event in AD and hence a potential target for therapeutic development, and moreover demonstrate a de novo multi-modal approach to derive information from rapidly increasing genomic datasets.

scholarly journals Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease

2020 ◽  
Vol 117 (41) ◽  
pp. 25800-25809 ◽  
Author(s):  
Shun-Fat Lau ◽  
Han Cao ◽  
Amy K. Y. Fu ◽  
Nancy Y. Ip
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Endothelial Cells ◽  
Transcriptome Analysis ◽  
Cell Type ◽  
Angiogenic Growth Factors ◽  
Cellular Targets ◽  
Therapeutic Development ◽  
Single Nucleus ◽  
Cell Type Specific

Alzheimer’s disease (AD) is the most common form of dementia but has no effective treatment. A comprehensive investigation of cell type-specific responses and cellular heterogeneity in AD is required to provide precise molecular and cellular targets for therapeutic development. Accordingly, we perform single-nucleus transcriptome analysis of 169,496 nuclei from the prefrontal cortical samples of AD patients and normal control (NC) subjects. Differential analysis shows that the cell type-specific transcriptomic changes in AD are associated with the disruption of biological processes including angiogenesis, immune activation, synaptic signaling, and myelination. Subcluster analysis reveals that compared to NC brains, AD brains contain fewer neuroprotective astrocytes and oligodendrocytes. Importantly, our findings show that a subpopulation of angiogenic endothelial cells is induced in the brain in patients with AD. These angiogenic endothelial cells exhibit increased expression of angiogenic growth factors and their receptors (i.e.,EGFL7,FLT1, andVWF) and antigen-presentation machinery (i.e.,B2MandHLA-E). This suggests that these endothelial cells contribute to angiogenesis and immune response in AD pathogenesis. Thus, our comprehensive molecular profiling of brain samples from patients with AD reveals previously unknown molecular changes as well as cellular targets that potentially underlie the functional dysregulation of endothelial cells, astrocytes, and oligodendrocytes in AD, providing important insights for therapeutic development.

scholarly journals Nanoscale Extracellular Vesicle Analysis in Alzheimer’s Disease Diagnosis and Therapy

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Pete Heinzelman ◽  
Tina Bilousova ◽  
Jesus Campagna ◽  
Varghese John
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Targets ◽  
Three Dimensional ◽  
Disease Diagnosis ◽  
Extracellular Vesicle ◽  
Current Status ◽  
New Therapeutic Approaches ◽  
Therapeutic Development ◽  
Diagnostic Applications

Diagnostic assays that leverage bloodborne neuron-derived (neuronal) nanoscale extracellular vesicles (nsEVs) as “windows into the brain” can predict incidence of Alzheimer’s Disease (AD) many years prior to onset. Beyond diagnostics, bloodborne neuronal nsEVs analysis may have substantial translational impact by revealing mechanisms of AD pathology; such knowledge could enlighten new drug targets and lead to new therapeutic approaches. The potential to establish three-dimensional nsEV analysis methods that characterize highly purified bloodborne nsEV populations in method of enrichment, cell type origin, and protein or RNA abundance dimensions could bring this promise to bear by yielding nsEV “omics” datasets that uncover new AD biomarkers and enable AD therapeutic development. In this review we provide a survey of both the current status of and new developments on the horizon in the field of neuronal nsEV analysis. This survey is supplemented by a discussion of the potential to translate such neuronal nsEV analyses to AD clinical diagnostic applications and drug development.

scholarly journals Post-Ischemic Neurodegeneration of the Hippocampus Resembling Alzheimer’s Disease Proteinopathy

2021 ◽  
Vol 23 (1) ◽  
pp. 306
Author(s):  
Ryszard Pluta ◽  
Sławomir Januszewski ◽  
Stanisław J. Czuczwar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Tissue ◽  
Blood Brain Barrier ◽  
Tau Protein ◽  
Amyloid Protein ◽  
Protein Precursor ◽  
Therapeutic Development ◽  
Development Goals ◽  
Hippocampal Neurodegeneration

In this review, we summarize, inter alia, the protein and gene changes associated with Alzheimer’s disease and their role in post-ischemic hippocampal neurodegeneration. In the hippocampus, studies have revealed dysregulation of the genes for the amyloid protein precursor metabolism and tau protein that is identical in nature to Alzheimer’s disease. Data indicate that amyloid and tau protein, derived from brain tissue and blood due to increased permeability of the blood–brain barrier after ischemia, play a key role in post-ischemic neurodegeneration of the hippocampus, with concomitant development of full-blown dementia. Thus, the knowledge of new neurodegenerative mechanisms that cause neurodegeneration of the hippocampus after ischemia, resembling Alzheimer’s disease proteinopathy, will provide the most important therapeutic development goals to date.

The Importance of Understanding Amylin Signaling Mechanisms for Therapeutic Development in the Treatment of Alzheimer’s Disease

2020 ◽  
Vol 26 (12) ◽  
pp. 1345-1355 ◽  
Author(s):  
Spencer Servizi ◽  
Rachel R. Corrigan ◽  
Gemma Casadesus
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Signaling Cascades ◽  
Complex Nature ◽  
Amyloid Accumulation ◽  
Therapeutic Development ◽  
Critical Insight ◽  
The Brain

Type II Diabetes (T2D) is a major risk factor for Alzheimer’s Disease (AD). These two diseases share several pathological features, including amyloid accumulation, inflammation, oxidative stress, cell death and cognitive decline. The metabolic hormone amylin and amyloid-beta are both amyloids known to self-aggregate in T2D and AD, respectively, and are thought to be the main pathogenic entities in their respective diseases. Furthermore, studies suggest amylin’s ability to seed amyloid-beta aggregation, the activation of common signaling cascades in the pancreas and the brain, and the ability of amyloid beta to signal through amylin receptors (AMYR), at least in vitro. However, paradoxically, non-aggregating forms of amylin such as pramlintide are given to treat T2D and functional and neuroprotective benefits of amylin and pramlintide administration have been reported in AD transgenic mice. These paradoxical results beget a deeper study of the complex nature of amylin’s signaling through the several AMYR subtypes and other receptors associated with amylin effects to be able to fully understand its potential role in mediating AD development and/or prevention. The goal of this review is to provide such critical insight to begin to elucidate how the complex nature of this hormone’s signaling may explain its equally complex relationship with T2D and mechanisms of AD pathogenesis.

Sexual dimorphism in behavior, neuropathology, and biomarkers in a tau P301S mouse model of Alzheimer’s disease

2019 ◽  
Author(s):  
Yao Sun ◽  
Yongqing Guo ◽  
Xuejian Feng ◽  
Meng Jia ◽  
Ning Ai ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Sexual Dimorphism ◽  
Transgenic Mice ◽  
Mouse Models ◽  
Building Performance ◽  
Inflammatory Protein ◽  
Model Of Alzheimer’S Disease ◽  
Age Related ◽  
Therapeutic Development

Abstract Tau hyper-phosphorylation has been considered a major contributor to neurodegeneration in Alzheimer’s disease (AD) and related tauopathies, and has gained prominence in therapeutic development for AD. To elucidate the pathogenic mechanisms underlying AD and evaluate therapeutic approaches targeting tau, numerous transgenic mouse models that recapitulate critical AD-like pathology have been developed. Tau P301S transgenic mice is one of the most widely used mouse models in AD research. Extensive studies have demonstrated that sex significantly influences AD pathology, behavioral status and therapeutic outcomes, suggesting that studies using mouse models of AD must consider sex- and age-related differences in neuropathology, behavior, and plasma content. Method: We systematically investigated differences in tau P301S transgenic mice (PS19 line) and wildtype littermates of different sex behavioral performance, tau neuropathology and biomarkers in plasma and brain. Results: Male P301S transgenic mice exhibited significant changes in weight loss, survival rate, clasping, kyphosis, composite phenotype assessment, nest building performance, tau phosphorylation at Ser202/Thr205 and astrocyte activation compared to that of wild type littermates. In contrast, female P301S transgenic mice were only sensitive in the Morris Water Maze and open field test. In addition, we characterized the upregulation of interferon (IFN)-γ, interleukin (IL)-5, and IL-6 and the absense of macrophage-inflammatory protein (MIP)-3α. Male P301S transgenic mice expressed more plasma biomarkers than those of female P301S mice. Conclusion: Our findings highlight sexual dimorphism in the behavior, neuropathology, and biomarkers in tau P301S transgenic AD mice, indicating that the use of male P301S transgenic mice may be more suitable for assessing anti-phosphorylated tau therapeutic strategies for AD and related tauopathies.

scholarly journals Arginine and Arginine-Rich Peptides as Modulators of Protein Aggregation and Cytotoxicity Associated With Alzheimer’s Disease

2021 ◽  
Vol 14 ◽  
Author(s):  
Somayra S. A. Mamsa ◽  
Bruno P. Meloni
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Aggregation ◽  
Amyloid Beta ◽  
Beneficial Effects ◽  
Therapeutic Development ◽  
Therapeutic Compounds ◽  
Tau Aggregation ◽  
Excitotoxic Cell Death

A substantial body of evidence indicates cationic, arginine-rich peptides (CARPs) are effective therapeutic compounds for a range of neurodegenerative pathologies, with beneficial effects including the reduction of excitotoxic cell death and mitochondrial dysfunction. CARPs, therefore, represent an emergent class of promising neurotherapeutics with multimodal mechanisms of action. Arginine itself is a known chaotrope, able to prevent misfolding and aggregation of proteins. The putative role of proteopathies in chronic neurodegenerative diseases such as Alzheimer’s disease (AD) warrants investigation into whether CARPs could also prevent the aggregation and cytotoxicity of amyloidogenic proteins, particularly amyloid-beta and tau. While monomeric arginine is well-established as an inhibitor of protein aggregation in solution, no studies have comprehensively discussed the anti-aggregatory properties of arginine and CARPs on proteins associated with neurodegenerative disease. Here, we review the structural, physicochemical, and self-associative properties of arginine and the guanidinium moiety, to explore the mechanisms underlying the modulation of protein aggregation by monomeric and multimeric arginine molecules. Arginine-rich peptide-based inhibitors of amyloid-beta and tau aggregation are discussed, as well as further modulatory roles which could reduce proteopathic cytotoxicity, in the context of therapeutic development for AD.

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