Neurodegenerative Diseases

2016 ◽  
Author(s):  
Jeffrey L. Cummings ◽  
Jagan A. Pillai
Keyword(s):  
Clinical Trials ◽  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Scientific Progress ◽  
Neuronal Loss ◽  
Therapeutic Interventions ◽  
Growth Factor Signaling ◽  
Age Related ◽  
Human Ips Cells ◽  
Neuropsychiatric Manifestations

Neurodegenerative diseases (NDDs) are growing in frequency and represent a major threat to public health. Advances in scientific progress have made it clear that NDDs share many underlying processes, including shared intracellular mechanisms such as protein misfolding and aggregation, cell-to-cell prion-like spread, growth factor signaling abnormalities, RNA and DNA disturbances, glial cell changes, and neuronal loss. Transmitter deficits are shared across many types of disorders. Means of studying NDDs with human iPS cells and transgenic models are similar. The progression of NDDs through asymptomatic, prodromal, and manifest stages is shared across disorders. Clinical features of NDDs, including cognitive impairment, disease progression, age-related effects, terminal stages, neuropsychiatric manifestations, and functional disorders and disability, have many common elements. Clinical trials, biomarkers, brain imaging, and regulatory aspects of NDD can share information across NDDs. Disease-modifying and transmitter-based therapeutic interventions, clinical trials, and regulatory approaches to treatments for NDDs are also similar.

scholarly journals ER stress in neurodegenerative disease: from disease mechanisms to therapeutic interventions

2017 ◽  
Vol 4 (1) ◽  
Author(s):  
Felipe Cabral-Miranda ◽  
Claudio Hetz
Keyword(s):  
Endoplasmic Reticulum ◽  
Neurodegenerative Diseases ◽  
Er Stress ◽  
Major Element ◽  
Neuronal Loss ◽  
Therapeutic Interventions ◽  
Unfolded Protein ◽  
Disease Mechanisms ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractThe conception that protein aggregates composed by misfolded proteins underlies the occurrence of several neurodegenerative diseases suggests that this phenomenon may have a common origin, ultimately driven by disruption of proteostasis control. The unfolded protein response (UPR) embodies a major element of the proteostasis network, which is engaged by endoplasmic reticulum (ER) stress. Chronic ER stress may operate as a possible mechanism of neurodegeneration, contributing to synaptic alterations, neuroinflammation and neuronal loss. In this review we discuss most recent findings relating ER stress and the development of distinct neurodegenerative diseases, and the possible strategies for disease intervention.

scholarly journals Contribution of Microglia-Mediated Neuroinflammation to Retinal Degenerative Diseases

2015 ◽  
Vol 2015 ◽  
pp. 1-15 ◽  
Author(s):  
Maria H. Madeira ◽  
Raquel Boia ◽  
Paulo F. Santos ◽  
António F. Ambrósio ◽  
Ana R. Santiago
Keyword(s):  
Vision Loss ◽  
Neuronal Loss ◽  
Age Related Macular Degeneration ◽  
Therapeutic Interventions ◽  
Degenerative Diseases ◽  
Disease Etiology ◽  
Neurodegenerative Process ◽  
Age Related ◽  
Retinal Microglia ◽  
Retinal Degenerative Diseases

Retinal degenerative diseases are major causes of vision loss and blindness worldwide and are characterized by chronic and progressive neuronal loss. One common feature of retinal degenerative diseases and brain neurodegenerative diseases is chronic neuroinflammation. There is growing evidence that retinal microglia, as in the brain, become activated in the course of retinal degenerative diseases, having a pivotal role in the initiation and propagation of the neurodegenerative process. A better understanding of the events elicited and mediated by retinal microglia will contribute to the clarification of disease etiology and might open new avenues for potential therapeutic interventions. This review aims at giving an overview of the roles of microglia-mediated neuroinflammation in major retinal degenerative diseases like glaucoma, age-related macular degeneration, and diabetic retinopathy.

scholarly journals Genome instability and loss of protein homeostasis: converging paths to neurodegeneration?

Open Biology ◽  
2021 ◽  
Vol 11 (4) ◽  
Author(s):  
Anna Ainslie ◽  
Wouter Huiting ◽  
Lara Barazzuol ◽  
Steven Bergink
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Neurodegenerative Diseases ◽  
Genome Stability ◽  
Genome Instability ◽  
Copy Number Variations ◽  
Therapeutic Interventions ◽  
Gene Copy ◽  
Protein Homeostasis ◽  
Age Related

Genome instability and loss of protein homeostasis are hallmark events of age-related diseases that include neurodegeneration. Several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis are characterized by protein aggregation, while an impaired DNA damage response (DDR) as in many genetic DNA repair disorders leads to pronounced neuropathological features. It remains unclear to what degree these cellular events interconnect with each other in the development of neurological diseases. This review highlights how the loss of protein homeostasis and genome instability influence one other. We will discuss studies that illustrate this connection. DNA damage contributes to many neurodegenerative diseases, as shown by an increased level of DNA damage in patients, possibly due to the effects of protein aggregates on chromatin, the sequestration of DNA repair proteins and novel putative DNA repair functions. Conversely, genome stability is also important for protein homeostasis. For example, gene copy number variations and the loss of key DDR components can lead to marked proteotoxic stress. An improved understanding of how protein homeostasis and genome stability are mechanistically connected is needed and promises to lead to the development of novel therapeutic interventions.

scholarly journals Novel PET Biomarkers to Disentangle Molecular Pathways across Age-Related Neurodegenerative Diseases

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2581
Author(s):  
Heather Wilson ◽  
Marios Politis ◽  
Eugenii A. Rabiner ◽  
Lefkos T. Middleton
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Imaging Technique ◽  
Emission Tomography ◽  
Imaging Biomarkers ◽  
Synaptic Dysfunction ◽  
Molecular Pathways ◽  
Age Related ◽  
Positron Emission

There is a need to disentangle the etiological puzzle of age-related neurodegenerative diseases, whose clinical phenotypes arise from known, and as yet unknown, pathways that can act distinctly or in concert. Enhanced sub-phenotyping and the identification of in vivo biomarker-driven signature profiles could improve the stratification of patients into clinical trials and, potentially, help to drive the treatment landscape towards the precision medicine paradigm. The rapidly growing field of neuroimaging offers valuable tools to investigate disease pathophysiology and molecular pathways in humans, with the potential to capture the whole disease course starting from preclinical stages. Positron emission tomography (PET) combines the advantages of a versatile imaging technique with the ability to quantify, to nanomolar sensitivity, molecular targets in vivo. This review will discuss current research and available imaging biomarkers evaluating dysregulation of the main molecular pathways across age-related neurodegenerative diseases. The molecular pathways focused on in this review involve mitochondrial dysfunction and energy dysregulation; neuroinflammation; protein misfolding; aggregation and the concepts of pathobiology, synaptic dysfunction, neurotransmitter dysregulation and dysfunction of the glymphatic system. The use of PET imaging to dissect these molecular pathways and the potential to aid sub-phenotyping will be discussed, with a focus on novel PET biomarkers.

scholarly journals Proteostasis Disturbances and Inflammation in Neurodegenerative Diseases

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2183
Author(s):  
Tuuli-Maria Sonninen ◽  
Gundars Goldsteins ◽  
Nihay Laham-Karam ◽  
Jari Koistinaho ◽  
Šárka Lehtonen
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Inflammatory Responses ◽  
Biological Response ◽  
Protein Damage ◽  
Protein Homeostasis ◽  
Cellular Functions ◽  
Regenerative Capacity ◽  
Age Related ◽  
Lateral Sclerosis

Protein homeostasis (proteostasis) disturbances and inflammation are evident in normal aging and some age-related neurodegenerative diseases. While the proteostasis network maintains the integrity of intracellular and extracellular functional proteins, inflammation is a biological response to harmful stimuli. Cellular stress conditions can cause protein damage, thus exacerbating protein misfolding and leading to an eventual overload of the degradation system. The regulation of proteostasis network is particularly important in postmitotic neurons due to their limited regenerative capacity. Therefore, maintaining balanced protein synthesis, handling unfolding, refolding, and degrading misfolded proteins are essential to preserve all cellular functions in the central nervous sysytem. Failing proteostasis may trigger inflammatory responses in glial cells, and the consequent release of inflammatory mediators may lead to disturbances in proteostasis. Here, we review the mechanisms of proteostasis and inflammatory response, emphasizing their role in the pathological hallmarks of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Furthermore, we discuss the interplay between proteostatic stress and excessive immune response that activates inflammation and leads to dysfunctional proteostasis.

scholarly journals Constructing the angiome: a global angiogenesis protein interaction network

2012 ◽  
Vol 44 (19) ◽  
pp. 915-924 ◽  
Author(s):  
Liang-Hui Chu ◽  
Corban G. Rivera ◽  
Aleksander S. Popel ◽  
Joel S. Bader
Keyword(s):  
Protein Interaction ◽  
Protein Interaction Network ◽  
Interaction Network ◽  
Age Related Macular Degeneration ◽  
Functional Enrichment ◽  
Therapeutic Interventions ◽  
Signaling Networks ◽  
Growth Factor Signaling ◽  
Age Related

Angiogenesis is the formation of new blood vessels from pre-existing microvessels. Excessive and insufficient angiogenesis have been associated with many diseases including cancer, age-related macular degeneration, ischemic heart, brain, and skeletal muscle diseases. A comprehensive understanding of angiogenesis regulatory processes is needed to improve treatment of these diseases. To identify proteins related to angiogenesis, we developed a novel integrative framework for diverse sources of high-throughput data. The system, called GeneHits, was used to expand on known angiogenesis pathways to construct the angiome, a protein-protein interaction network for angiogenesis. The network consists of 478 proteins and 1,488 interactions. The network was validated through cross validation and analysis of five gene expression datasets from in vitro angiogenesis assays. We calculated the topological properties of the angiome. We analyzed the functional enrichment of angiogenesis-annotated and associated proteins. We also constructed an extended angiome with 1,233 proteins and 5,726 interactions to derive a more complete map of protein-protein interactions in angiogenesis. Finally, the extended angiome was used to identify growth factor signaling networks that drive angiogenesis and antiangiogenic signaling networks. The results of this analysis can be used to identify genes and proteins in different disease conditions and putative targets for therapeutic interventions as high-ranked candidates for experimental validation.

scholarly journals BIOMARKERS OF SARCOPENIA IN CLINICAL TRIALS RECOMMENDATIONS FROM THE INTERNATIONAL WORKING GROUP ON SARCOPENIA

2012 ◽  
pp. 1-9
Author(s):  
M. CESARI ◽  
R.A. FIELDING ◽  
M. PAHOR ◽  
B. GOODPASTER ◽  
M. HELLERSTEIN ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Clinical Trials ◽  
Working Group ◽  
Task Force ◽  
Scientific Progress ◽  
Health Priorities ◽  
International Working Group ◽  
Age Related ◽  
The Subject ◽  
Preliminary Phase

Sarcopenia, the age-related skeletal muscle decline, is associated with relevant clinical and socioeconomic negative outcomes in older persons. The study of this phenomenon and the development of preventive/therapeutic strategies represent public health priorities. The present document reports the results of a recent meeting of the International Working Group on Sarcopenia (a task force consisting of geriatricians and scientists from academia and industry) held on June 7-8, 2011 in Toulouse (France). The meeting was specifically focused at gaining knowledge on the currently available biomarkers (functional, biological, or imaging-related) that could be utilized in clinical trials of sarcopenia and considered the most reliable and promising to evaluate age-related modifications of skeletal muscle. Specific recommendations about the assessment of aging skeletal muscle in older people and the optimal methodological design of studies on sarcopenia were also discussed and finalized. Although the study of skeletal muscle decline is still in a very preliminary phase, the potential great benefits derived from a better understanding and treatment of this condition should encourage research on sarcopenia. However, the reasonable uncertainties (derived from exploring a novel field and the exponential acceleration of scientific progress) require the adoption of a cautious and comprehensive approach to the subject.

scholarly journals Age-Dependent Levels of Protein Kinase Cs in Brain: Reduction of Endogenous Mechanisms of Neuroprotection

2019 ◽  
Vol 20 (14) ◽  
pp. 3544
Author(s):  
Donatella Pastore ◽  
Francesca Pacifici ◽  
Kunjan R. Dave ◽  
Raffaele Palmirotta ◽  
Alfonso Bellia ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Neurodegenerative Diseases ◽  
Neuronal Loss ◽  
Cognitive Disorders ◽  
Original Data ◽  
Therapeutic Approaches ◽  
Age Related ◽  
Causes Of Mortality ◽  
Cognitive Diseases ◽  
Prevention And Cure

Neurodegenerative diseases are among the leading causes of mortality and disability worldwide. However, current therapeutic approaches have failed to reach significant results in their prevention and cure. Protein Kinase Cs (PKCs) are kinases involved in the pathophysiology of neurodegenerative diseases, such as Alzheimer’s Disease (AD) and cerebral ischemia. Specifically ε, δ, and γPKC are associated with the endogenous mechanism of protection referred to as ischemic preconditioning (IPC). Existing modulators of PKCs, in particular of εPKC, such as ψεReceptor for Activated C-Kinase (ψεRACK) and Resveratrol, have been proposed as a potential therapeutic strategy for cerebrovascular and cognitive diseases. PKCs change in expression during aging, which likely suggests their association with IPC-induced reduction against ischemia and increase of neuronal loss occurring in senescent brain. This review describes the link between PKCs and cerebrovascular and cognitive disorders, and proposes PKCs modulators as innovative candidates for their treatment. We report original data showing εPKC reduction in levels and activity in the hippocampus of old compared to young rats and a reduction in the levels of δPKC and γPKC in old hippocampus, without a change in their activity. These data, integrated with other findings discussed in this review, demonstrate that PKCs modulators may have potential to restore age-related reduction of endogenous mechanisms of protection against neurodegeneration.

scholarly journals Endocannabinoid Signaling for GABAergic-Microglia (Mis)Communication in the Brain Aging

2021 ◽  
Vol 14 ◽  
Author(s):  
Jorge Carrera ◽  
Jensen Tomberlin ◽  
John Kurtz ◽  
Eda Karakaya ◽  
Mehmet Bostanciklioglu ◽  
...  
Keyword(s):  
Communication System ◽  
Brain Aging ◽  
Neuronal Loss ◽  
Endocannabinoid System ◽  
Therapeutic Interventions ◽  
Aging Brain ◽  
Age Related ◽  
The Brain ◽  
Excessive Activation ◽  
By Products

The aging brain seems to be characterized by neuronal loss leading to cognitive decline and progressively worsening symptoms related to neurodegeneration. Also, pro-inflammatory states, if prolonged, may increase neuronal vulnerability via excessive activation of microglia and their pro-inflammatory by-products, which is seen as individuals increase in age. Consequently, microglial activity is tightly regulated by neuron-microglia communications. The endocannabinoid system (ECS) is emerging as a regulator of microglia and the neuronal-microglia communication system. Recently, it has been demonstrated that cannabinoid 1 (CB1) receptor signaling on GABAergic interneurons plays a crucial role in regulating microglial activity. Interestingly, if endocannabinoid signaling on GABAergic neurons are disturbed, the phenotypes mimic central nervous system insult models by activating microglia and leading to accelerated brain aging. Investigating the endocannabinoid receptors, ligands, and genetic deletions yields the potential to understand the communication system and mechanism by which the ECS regulates glial cells and aspects of aging. While there remains much to discover with the ECS, the information gathered and identified already could lead to the development of cell-specific therapeutic interventions that help in reducing the effects of age-related pro-inflammatory states and neurodegeneration.

Advances in Our Understanding of the Pathophysiology of Alzheimer’s Disease

US Neurology ◽  
2010 ◽  
Vol 06 (01) ◽  
pp. 28 ◽  
Author(s):  
Kim N Green ◽  
Steven S Schreiber ◽  
◽  
Keyword(s):  
Symptomatic Relief ◽  
Neuronal Loss ◽  
Current Understanding ◽  
Therapeutic Interventions ◽  
Disease Modification ◽  
The Past ◽  
Age Related ◽  
The Us ◽  
Alois Alzheimer ◽  
The Brain

Alzheimer’s disease (AD) is the most common age-related dementia, currently affecting more than 5 million patients in the US alone, and is characterized by the presence of both extracellular plaques and intraneuronal tangles in the brain of a patient with dementia. Alois Alzheimer first described the pathology associated with the disease over 100 years ago, and during the past three decades our understanding of the disease and of potential ways to treat it has increased tremendously. In this article we describe our current understanding of both the pathophysiology of Alzheimer’s disease and current and future therapeutic interventions, including symptomatic relief, disease modification, and the reversal of synaptic and neuronal loss.

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