Abstract:
:Age-progressive neurodegenerative pathologies, including Alzheimer's disease (AD), are distinguished and diagnosed by disease-specific components of intra- or extra-cellular aggregates. Increasing evidence suggests that neuroinflammation promotes protein aggregation, and is involved in the etiology of neurological diseases. We synthesized and tested analogs of the naturally occurring tubulin-binding compound, combretastatin A-4. One such analog, PNR502, markedly reduced the quantity of Alzheimer-associated amyloid aggregates in the BRI-Aβ1-42 mouse model of AD, while blunting the ability of the pro-inflammatory cytokine IL-1β to raise levels of amyloid plaque and its protein precursors in a neuronal cell-culture model. In transgenic Caenorhabditis elegans (C. elegans) strains that express human Aβ1-42 in muscle or neurons, PNR502 rescued Aβ-induced disruption of motility (3.8-fold, P < 0.0001) or chemotaxis (1.8-fold, P < 0.05), respectively. Moreover, in C. elegans with neuronal expression of Aβ1-42, a single day of PNR502 exposure reverses the chemotaxis deficit by 54% (P < 0.01), actually exceeding the protection from longer exposure. Moreover, continuous PNR502 treatment extends nematode lifespan 23% (P ≤ 0.001). Given that PNR502 can slow, prevent, or reverse Alzheimer-like protein aggregation in human-cell-culture and animal models, and that its principal predicted and observed binding targets are proteins previously implicated in Alzheimer's, we propose that PNR502 has therapeutic potential to inhibit cerebral Aβ1-42 aggregation and prevent or reverse neurodegeneration.
journal_name
Front Mol Neuroscijournal_title
Frontiers in molecular neuroscienceauthors
Kakraba S,Ayyadevara S,Penthala NR,Balasubramaniam M,Ganne A,Liu L,Alla R,Bommagani SB,Barger SW,Griffin WST,Crooks PA,Shmookler Reis RJdoi
10.3389/fnmol.2019.00310subject
Has Abstractpub_date
2019-12-12 00:00:00pages
310issn
1662-5099journal_volume
12pub_type
杂志文章abstract::Ischemic stroke is one of the most common causes of death and disability worldwide. Neuroinflammation is a major pathological event involved in the process of ischemic injury and repair. In particular, microglia play a dual role in neuroinflammation. During the acute phase of stroke onset, M2 microglia are the dominan...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2020.612439
更新日期:2021-01-07 00:00:00
abstract::Alzheimer's disease (AD) is a progressive disease with early degeneration of the central cholinergic neurons. Currently, three of four AD drugs act by inhibiting the acetylcholine (ACh) degrading enzyme, acetylcholinesterase (AChE). Efficacy of these drugs depends on available amount of ACh, which is biosynthesized by...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2019.00239
更新日期:2019-10-11 00:00:00
abstract::In this review we provide an overview of key in vivo experiments undertaken in the cat spinal cord in the 1950s and 1960s, and point out their contributions to our present understanding of glycine receptor (GlyR) function. Importantly, some of these discoveries were made well before an inhibitory receptor, or its agon...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2010.00013
更新日期:2010-05-21 00:00:00
abstract::Medical marijuana is increasingly prescribed as an analgesic for a growing number of indications, amongst which terminal cancer and multiple sclerosis. However, the mechanistic aspects and properties of cannabis remain remarkably poorly characterized. In this study we aimed to investigate the immune-cell modulatory pr...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2017.00014
更新日期:2017-01-24 00:00:00
abstract::Spinal cord injury (SCI) causes the death of neurons and glial cells due to the initial mechanical forces (i.e., primary injury) and through a cascade of secondary molecular events (e.g., inflammation or excitotoxicity) that exacerbate cell death. The loss of neurons and glial cells that are not replaced after the inj...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2018.00101
更新日期:2018-04-03 00:00:00
abstract::Corticotropin releasing factor (CRF) has been shown to induce various behavioral changes related to adaptation to stress. Dysregulation of the CRF system at any point can lead to a variety of psychiatric disorders, including substance use disorders (SUDs). CRF has been associated with stress-induced drug reinforcement...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2012.00091
更新日期:2012-09-06 00:00:00
abstract::[This corrects the article DOI: 10.3389/fnmol.2019.00099.]. ...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,已发布勘误
doi:10.3389/fnmol.2019.00149
更新日期:2019-06-12 00:00:00
abstract::Microglial activation and the inflammatory response in the central nervous system (CNS) play important roles in secondary damage after traumatic brain injury (TBI). Transcriptional activation of genes that limit secondary damage to the CNS are mediated by a cis-acting element called the antioxidant responsive element ...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2018.00117
更新日期:2018-04-17 00:00:00
abstract::In the last decade, bioinformatic analyses of high-throughput proteomics and transcriptomics data have enabled researchers to gain insight into the molecular networks that may underlie lasting changes in synaptic efficacy. Development and utilization of these techniques have advanced the field of learning and memory s...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2017.00045
更新日期:2017-02-24 00:00:00
abstract::Ca2+ signaling plays a significant role in the development of the vertebrate nervous system where it regulates neurite growth as well as synapse and neurotransmitter specification. Elucidating the role of Ca2+ signaling in mammalian neuronal development has been largely restricted to either small animal models or prim...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2018.00178
更新日期:2018-06-11 00:00:00
abstract::Neuroblastoma is a neural crest derived malignancy of the peripheral nervous system and is the most common and deadliest tumor of infancy. It is characterized by clinical heterogeneity with a disease spectrum ranging from spontaneous regression without any medical intervention to treatment resistant tumors with metast...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2019.00009
更新日期:2019-01-29 00:00:00
abstract::In the brain, metabolic supply and demand is directly coupled to neuronal activation. Methods for culturing primary rodent brain cells have come of age and are geared toward sophisticated modeling of human brain physiology and pathology. However, the impact of the culture microenvironment on neuronal function is rarel...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2017.00305
更新日期:2017-09-29 00:00:00
abstract::Proteolytic processing of the Amyloid Precursor Protein (APP) produces beta-amyloid (Aβ) peptide fragments that accumulate in Alzheimer's Disease (AD), but APP may also regulate multiple aspects of neuronal development, albeit via mechanisms that are not well understood. APP is a member of a family of transmembrane gl...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2016.00130
更新日期:2016-11-25 00:00:00
abstract::N-methyl-D-aspartate receptors (NMDARs) play critical roles in both excitatory neurotransmission and synaptic plasticity. NMDARs containing the nonconventional GluN3A subunit have different functional properties compared to receptors comprised of GluN1/GluN2 subunits. Previous studies showed that GluN1/GluN2 receptors...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2018.00188
更新日期:2018-06-04 00:00:00
abstract::Parkinson's disease (PD) is a progressive CNS disorder that is primarily associated with impaired movement. PD develops over decades and is linked to the gradual loss of dopamine delivery to the striatum, via the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). While the administration o...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2019.00010
更新日期:2019-02-11 00:00:00
abstract::Epilepsy, one of the most prevalent neurological conditions, presents as a complex disorder of network homeostasis characterized by spontaneous non-provoked seizures and associated comorbidities. Currently used antiepileptic drugs have been designed to suppress neuronal hyperexcitability and thereby to suppress epilep...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2016.00026
更新日期:2016-04-13 00:00:00
abstract::Mitochondrial dysfunction is a prominent trait of cellular decline during aging and intimately linked to neuronal degeneration during Parkinson's disease (PD). Various proteins associated with PD have been shown to differentially impact mitochondrial dynamics, quality control and function, including the leucine-rich r...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2018.00205
更新日期:2018-06-21 00:00:00
abstract::Long-term potentiation (LTP) and long-term depression (LTD) are two major forms of synaptic plasticity that are widely accepted as cellular mechanisms involved in learning and memory. Metaplasticity is a process whereby modifications in synaptic processes shift the threshold for subsequent plasticity. While metaplasti...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2019.00322
更新日期:2020-01-24 00:00:00
abstract::The impairment of amyloid-β (Aβ) clearance in the brain plays a causative role in Alzheimer's disease (AD). Polarity distribution of aquaporin-4 (AQP4) is important to remove Aβ from brain. AQP4 polarity can be influenced by the ratio of two AQP4 isoforms M1 and M23 (AQP4-M1/M23), however, it is unknown whether the ra...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2017.00395
更新日期:2017-11-29 00:00:00
abstract::Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. It is caused by the overexpansion of cytosine-guanine-guanine (CGG) trinucleotide in Fmr1 gene, resulting in complete loss of the fragile X mental retardation protein (FMRP). Previous studies using Fmr1 knockout (Fmr1 KO) mice have ...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2018.00495
更新日期:2019-01-17 00:00:00
abstract::In the past two decades, yeast models have delivered profound insights into basic mechanisms of protein misfolding and the dysfunction of key cellular pathways associated with amyotrophic lateral sclerosis (ALS). Expressing ALS-associated proteins, such as superoxide dismutase (SOD1), TAR DNA binding protein 43 (TDP-4...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2018.00394
更新日期:2018-10-30 00:00:00
abstract::Neuronal gap junctions formed by connexin36 (Cx36) and chemical synapses share striking similarities in terms of plasticity. Ca2+/calmodulin-dependent protein kinase II (CaMKII), an enzyme known to induce memory formation at chemical synapses, has recently been described to potentiate electrical coupling in the retina...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2019.00206
更新日期:2019-08-28 00:00:00
abstract::Connexin channels play numerous essential roles in virtually every organ by mediating solute exchange between adjacent cells, or between cytoplasm and extracellular milieu. Our understanding of the structure-function relationship of connexin channels relies on X-ray crystallographic data for human connexin 26 (hCx26) ...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2018.00170
更新日期:2018-05-31 00:00:00
abstract::Alzheimer's disease (AD) is a widely distributed neurodegenerative disease characterized clinically by cognitive deficits and pathologically by formation of amyloid-β (Aβ) plaque and neurofibrillary tangles (NFTs) in the brain. Vanadium is a biological trace element that has a function to mimic insulin for diabetes. B...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2020.00021
更新日期:2020-03-10 00:00:00
abstract::Stroke results in high morbidity and high mortality worldwide, with ischemic stroke accounting for 80% to 85%. As effective treatments for ischemic stroke remain limited because of the narrow therapeutic time window, a better understanding of the pathologic mechanism and new therapeutic intervention targets are needed...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章,评审
doi:10.3389/fnmol.2019.00061
更新日期:2019-03-22 00:00:00
abstract::Lithium has long been used for the treatment of psychiatric disorders, due to its robust beneficial effect as a mood stabilizing drug. Lithium's effectiveness for improving neurological function is therefore well-described, stimulating the investigation of its potential use in several neurodegenerative conditions incl...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2018.00297
更新日期:2018-08-28 00:00:00
abstract::Neuroimaging studies have demonstrated that irritable bowel syndrome (IBS)-a relapsing functional bowel disorder-presents with disrupted brain connections. However, little is known about the alterations of interhemispheric functional connectivity and underlying structural connectivity in IBS. This study combined resti...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2016.00141
更新日期:2016-12-06 00:00:00
abstract::The brain contains an enormous, but finite, number of neurons. The ability of this limited number of neurons to produce nearly limitless neural information over a lifetime is typically explained by combinatorial explosion; that is, by the exponential amplification of each neuron's contribution through its incorporatio...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2012.00045
更新日期:2012-04-12 00:00:00
abstract::We earlier reported that the male mice lacking the Wdr13 gene (Wdr13-/0) showed mild anxiety, better memory retention, and up-regulation of synaptic proteins in the hippocampus. With increasing evidences from parallel studies in our laboratory about the possible role of Wdr13 in stress response, we investigated its ro...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2018.00133
更新日期:2018-04-25 00:00:00
abstract::Cytoplasmic FMR1-interacting protein 2 (CYFIP2) is a key component of the WAVE regulatory complex (WRC) which regulates actin polymerization and branching in diverse cellular compartments. Recent whole exome sequencing studies identified de novo hotspot variants in CYFIP2 from patients with early-onset epileptic encep...
journal_title:Frontiers in molecular neuroscience
pub_type: 杂志文章
doi:10.3389/fnmol.2018.00482
更新日期:2019-01-04 00:00:00