Juliet Klasing Knowles
Assistant Professor of Neurology and Neurological Sciences (Pediatric Neurology) and of Pediatrics
Bio
Juliet Knowles is Assistant Professor in Neurology at Stanford. Dr. Knowles is a physician-scientist who provides clinical care for children with epilepsy and leads a lab team conducting basic, translational and clinical research on pediatric epilepsy. She completed her M.D. and Ph.D. in Neurosciences at Stanford University, followed by residency training in Pediatrics and Child Neurology at Stanford, where she also served as Chief Resident. Following clinical fellowship training in Pediatric Epilepsy, Dr. Knowles completed post-doctoral research related to myelin plasticity in epilepsy, under the mentorship of Drs. Michelle Monje and John Huguenard. Dr. Knowles is passionate about providing thorough, compassionate and innovative care for her patients, and her overarching goal is to use research as a tool to discover improved therapies for children with epilepsy. She is committed to mentoring the next generation of scientists and clinicians, from undergraduates interested in learning about lab research to medical students, residents and post-doctoral scholars. When she is not in the clinic or the lab, Dr. Knowles loves to spend time with her husband, Josh, and their two children. She also enjoys reading, training and running in marathons, and spending time in the great outdoors of California.
Clinical Focus
- Pediatric Epilepsy
- Epilepsy
Academic Appointments
-
Assistant Professor - University Medical Line, Neurology
-
Assistant Professor - University Medical Line, Pediatrics
-
Member, Bio-X
Honors & Awards
-
Stroup Award for Rising Star in Epilepsy, Johns Hopkins University (2021)
-
Elterman Research Award, Pediatric Epilepsy Research Foundation (2020)
-
First place, Stanford Neuroscience Research Forum, Stanford University (2016)
-
Outstanding Young Scientist Award, Northern California Alzheimer's Association (2009)
Boards, Advisory Committees, Professional Organizations
-
Scientific Program Committee, American Epilepsy Society (2021 - Present)
-
Research Committee, Child Neurology Society (2020 - Present)
Professional Education
-
Board Certification: American Board of Psychiatry and Neurology, Neurology with Special Qualifications in Child Neurology (2016)
-
Internship: Stanford Health Care at Lucile Packard Children's Hospital (2013) CA
-
Medical Education: Stanford University School of Medicine (2011) CA
-
Board Certification: American Board of Psychiatry and Neurology, Epilepsy (2018)
-
Fellowship: Stanford University Pediatric Epilepsy Fellowship (2018) CA
-
Residency: Stanford University Child Neurology Residency (2016) CA
Research Interests
-
Brain and Learning Sciences
-
Research Methods
Current Research and Scholarly Interests
Epilepsy affects ~1% of all children and is defined by recurrent, unprovoked seizures, impaired cognitive abilities, and diminished quality of life. The predisposition for seizures is thought to result from abnormal plasticity and excessive synchrony in affected neural networks. Myelin plasticity is a newly recognized mode of activity-dependent neural network adaptation. The potential for dysregulated myelin plasticity in disease states such as epilepsy is unexplored. Myelination of axons increases conduction velocity and promotes coordinated network function including oscillatory synchrony. During and after age-dependent developmental myelination, increases in myelin occur when humans and rodents acquire new skills. While adaptive myelin plasticity modulates networks to support function in the healthy state, it is unknown whether this process also contributes to network dysfunction in neurological disease.
The Knowles lab conducts basic, translational and clinical research to study how seizures shape white matter, and how changes in white matter shape the course of epilepsy and its co-morbidities. We discovered that generalized (absence) seizures induce aberrant myelination that promotes seizure progression. Thus, maladaptive myelination may be a novel pathogenic mechanism in epilepsy and other neurological diseases. Using innovative imaging, electrophysiological, histological and molecular biology techniques, we are studying multiple questions.
-How does white matter structure change throughout the brain over the course of epilepsy?
-How does white matter structure impact network synchronization, seizures and cognition?
-What signaling pathways underlie aberrant white matter plasticity in different forms of epilepsy?
-What can we learn from white matter changes found with various imaging modalities in humans with epilepsy?
Our overarching goals are to better understand how epilepsy occurs and to develop treatments that improve the lives of children with epilepsy.
2024-25 Courses
-
Independent Studies (7)
- Directed Reading in Neurosciences
NEPR 299 (Aut, Win, Spr, Sum) - Graduate Research
NEPR 399 (Aut, Sum) - Honors
HUMBIO 194 (Spr) - Out-of-Department Graduate Research
BIO 300X (Aut, Win, Spr) - Out-of-Department Undergraduate Research
BIO 199X (Aut, Win, Spr) - Research in Human Biology
HUMBIO 193 (Aut, Win) - Undergraduate Research
NENS 199 (Aut, Win, Spr, Sum)
- Directed Reading in Neurosciences
Stanford Advisees
-
Postdoctoral Faculty Sponsor
Azin Ebrahim Amini, Lei Peng, Kala Prasannalatha Nair -
Doctoral Dissertation Co-Advisor (NonAC)
Nour Omar -
Doctoral Dissertation Reader (NonAC)
Clara Bacmeister, Shreya Malhotra, Emma O'Connell
All Publications
-
Attentional Deficits and Absence Epilepsy: A Tale of 2 Interneuronopathies.
Epilepsy currents
2024; 24 (3): 188-190
View details for DOI 10.1177/15357597241251709
View details for PubMedID 38898911
View details for PubMedCentralID PMC11185201
-
Attentional Deficits and Absence Epilepsy: A Tale of 2 Interneuronopathies
EPILEPSY CURRENTS
2024
View details for DOI 10.1177/15357597241251709
View details for Web of Science ID 001222329000001
-
Quantitative MRI reveals widespread, network-specific myelination change during generalized epilepsy progression.
NeuroImage
2023: 120312
Abstract
Activity-dependent myelination is a fundamentally important mode of brain plasticity which significantly influences function. We recently discovered that absence seizures, which occur in multiple forms of generalized epilepsy, can induce activity-dependent myelination, which in turn promotes further progression of epilepsy. Structural alterations of myelin are likely to be widespread, given that absence seizures arise from an extensive thalamocortical network involving frontoparietal regions of the bilateral hemispheres. However, the temporal course and spatial extent of myelin plasticity is unknown, due to limitations of gold-standard histological methods such as electron microscopy (EM). In this study, we leveraged magnetization transfer and diffusion MRI for estimation of g-ratios across major white matter tracts in a mouse model of generalized epilepsy with progressive absence seizures. Electron microscopy was performed on the same brains after MRI. After seizure progression, we found increased myelination (decreased g-ratios) throughout the anterior portion (genu-to-body) of the corpus callosum but not in the posterior portion (body-splenium) nor in the fornix or the internal capsule. Curves obtained from averaging g-ratio values at every longitudinal point of the corpus callosum were statistically different with p<0.0001. Seizure-associated myelin differences found in the corpus callosum body with MRI were statistically significant (p = 0.0027) and were concordant with EM in the same region (p = 0.01). Notably, these differences were not detected by diffusion tensor imaging. This study reveals widespread myelin structural change that is specific to the absence seizure network.Furthermore, our findings demonstrate the potential utility and importance of MRI-based g-ratio estimation to non-invasively detect myelin plasticity.
View details for DOI 10.1016/j.neuroimage.2023.120312
View details for PubMedID 37574120
-
Adaptive and maladaptive myelination in health and disease.
Nature reviews. Neurology
2022
Abstract
Within the past decade, multiple lines of evidence have converged to identify a critical role for activity-regulated myelination in tuning the function of neural networks. In this Review, we provide an overview of accumulating evidence that activity-regulated myelination is required for brain adaptation and learning across multiple domains. We then discuss dysregulation of activity-dependent myelination in the context of neurological disease, a novel frontier with the potential to uncover new mechanisms of disease pathogenesis and to develop new therapeutic strategies. Alterations in myelination and neural network function can result from deficient myelin plasticity that impairs neurological function or from maladaptive myelination, in which intact activity-dependent myelination contributes to the disease process by promoting pathological patterns of neuronal activity. These emerging mechanisms suggest new avenues for therapeutic intervention that could more fully address the complex interactions between neurons and oligodendroglia.
View details for DOI 10.1038/s41582-022-00737-3
View details for PubMedID 36376595
-
Maturation and circuit integration of transplanted human cortical organoids.
Nature
2022; 610 (7931): 319-326
Abstract
Self-organizing neural organoids represent a promising in vitro platform with which to model human development and disease1-5. However, organoids lack the connectivity that exists in vivo, which limits maturation and makes integration with other circuits that control behaviour impossible. Here we show that human stem cell-derived cortical organoids transplanted into the somatosensory cortex of newborn athymic rats develop mature cell types that integrate into sensory and motivation-related circuits. MRI reveals post-transplantation organoid growth across multiple stem cell lines and animals, whereas single-nucleus profiling shows progression of corticogenesis and the emergence of activity-dependent transcriptional programs. Indeed, transplanted cortical neurons display more complex morphological, synaptic and intrinsic membrane properties than their in vitro counterparts, which enables the discovery of defects in neurons derived from individuals with Timothy syndrome. Anatomical and functional tracings show that transplanted organoids receive thalamocortical and corticocortical inputs, and in vivo recordings of neural activity demonstrate that these inputs can produce sensory responses in human cells. Finally, cortical organoids extend axons throughout the rat brain and their optogenetic activation can drive reward-seeking behaviour. Thus, transplanted human cortical neurons mature and engage host circuits that control behaviour. We anticipate that this approach will be useful for detecting circuit-level phenotypes in patient-derived cells that cannot otherwise be uncovered.
View details for DOI 10.1038/s41586-022-05277-w
View details for PubMedID 36224417
-
Precision medicine for genetic epilepsy on the horizon: recent advances, present challenges and suggestions for continued progress.
Epilepsia
2022
Abstract
The genetic basis of many epilepsies is increasingly understood, giving rise to the possibility of precision treatments tailored to specific genetic etiologies. Despite this, current medical therapy for most epilepsies remains imprecise, aimed primarily at empirical seizure reduction rather than targeting specific disease processes. Intellectual and technological leaps in diagnosis over the last ten years have not yet translated to routine changes in clinical practice. However, the epilepsy community is poised to make impressive gains in precision therapy with continued innovation in gene discovery, diagnostic ability and bioinformatics; increased access to genetic testing and counseling; fuller understanding of natural histories; agility and rigor in preclinical research, including strategic use of emerging model systems; and engagement of an evolving group of stakeholders (including patient advocates, governmental resources, and clinicians and scientists in academia and industry). In each of these areas, we highlight notable examples of recent progress, new or persistent challenges and future directions. The future of precision medicine for genetic epilepsy looks bright if key opportunities on the horizon can be pursued with strategic and coordinated effort.
View details for DOI 10.1111/epi.17332
View details for PubMedID 35716052
-
Maladaptive myelination promotes generalized epilepsy progression.
Nature neuroscience
2022
Abstract
Activity-dependent myelination can fine-tune neural network dynamics. Conversely, aberrant neuronal activity, as occurs in disorders of recurrent seizures (epilepsy), could promote maladaptive myelination, contributing to pathogenesis. In this study, we tested the hypothesis that activity-dependent myelination resulting from absence seizures, which manifest as frequent behavioral arrests with generalized electroencephalography (EEG) spike-wave discharges, promote thalamocortical network hypersynchrony and contribute to epilepsy progression. We found increased oligodendrogenesis and myelination specifically within the seizure network in two models of generalized epilepsy with absence seizures (Wag/Rij rats and Scn8a+/mut mice), evident only after epilepsy onset. Aberrant myelination was prevented by pharmacological seizure inhibition in Wag/Rij rats. Blocking activity-dependent myelination decreased seizure burden over time and reduced ictal synchrony as assessed by EEG coherence. These findings indicate that activity-dependent myelination driven by absence seizures contributes to epilepsy progression; maladaptive myelination may be pathogenic in some forms of epilepsy and other neurological diseases.
View details for DOI 10.1038/s41593-022-01052-2
View details for PubMedID 35501379
-
Practical Advice on Surviving and Thriving as an Academic Physician-Neuroscientist.
JAMA neurology
2021
View details for DOI 10.1001/jamaneurol.2021.3889
View details for PubMedID 34694341
-
A Standardized Protocol to Improve Acute Seizure Management in Hospitalized Pediatric Patients.
Hospital pediatrics
2021
Abstract
BACKGROUND: Studies of seizure management in the pediatric inpatient setting are needed. Seizures recorded by video EEG provide an opportunity to quantitatively evaluate acute management. We observed variation in delivery of standardized seizure safety measures (seizure first aid) during epilepsy monitoring unit admissions at our hospital. Our goals were to increase consistency and speed of seizure first aid and neurologic assessment in acutely seizing patients.METHODS: Using a root cause analysis, we identified major factors contributing to variation in seizure management and key drivers for improvement. Targeted interventions, centered around a protocol for acute seizure management, were implemented through quality improvement methodology. The primary outcome was correct performance of standardized seizure first aid and neurologic assessment. Secondary outcomes were time intervals to each assessment. Run charts were used to analyze primary outcomes, and statistical control charts were used for secondary outcomes. Nursing confidence in seizure management was determined through pre- and postsurveys and analyzed with the chi2 test.RESULTS: Thirteen seizures were evaluated in the preintervention phase and 10 in the postintervention phase. Completed components of seizure first aid increased from a median of 3 of 4 to 4 of 4; completed components of neurologic assessment increased from a median of 2 of 4 to 4 of 4. Responses to acute seizures were faster, and nursing confidence increased.CONCLUSIONS: A collaborative quality improvement effort between physicians and nurses led to prompt and correct delivery of seizure first aid by first responders. These relatively simple interventions could be adapted broadly to improve acute seizure management in the pediatric inpatient setting.
View details for DOI 10.1542/hpeds.2020-000968
View details for PubMedID 33685859
-
Improving Bedside Seizure Care of Pediatric Epilepsy Monitoring Unit (EMU) Patients: Creation and Implementation of a Standardized Protocol
LIPPINCOTT WILLIAMS & WILKINS. 2020
View details for Web of Science ID 000536058005062
-
Neonatal genetic epilepsies display convergent white matter microstructural abnormalities.
Epilepsia
2020
Abstract
White matter undergoes rapid development in the neonatal period. Its structure during and after development is influenced by neuronal activity. Pathological neuronal activity, as in seizures, might alter white matter, which in turn may contribute to network dysfunction. Neonatal epilepsy presents an opportunity to investigate seizures and early white matter development. Our objective was to determine whether neonatal seizures in the absence of brain injury or congenital anomalies are associated with altered white matter microstructure. In this retrospective case-control study of term neonates, cases had confirmed or suspected genetic epilepsy and normal brain magnetic resonance imaging (MRI) and no other conditions independently impacting white matter. Controls were healthy neonates with normal MRI results. White matter microstructure was assessed via quantitative mean diffusivity (MD). In 22 cases, MD was significantly lower in the genu of the corpus callosum, compared to 22 controls, controlling for gestational age and postmenstrual age at MRI. This finding suggests convergent abnormal corpus callosum microstructure in neonatal epilepsies with diverse suspected genetic causes. Further study is needed to determine the specific nature, causes, and functional impact of seizure-associated abnormal white matter in neonates, a potential pathogenic mechanism.
View details for DOI 10.1111/epi.16735
View details for PubMedID 33098118
-
Refractory focal epilepsy in a paediatric patient with primary familial brain calcification.
Seizure
2018; 56: 50–52
Abstract
Primary familial brain calcification (PFBC), otherwise known as Fahr's disease, is a rare autosomal dominant condition with manifestations of movement disorders, neuropsychiatric symptoms, and epilepsy in a minority of PFBC patients. The clinical presentation of epilepsy in PFBC has not been described in detail. We present a paediatric patient with PFBC and refractory focal epilepsy based on seizure semiology and ictal EEG, but with generalized interictal EEG abnormalities. The patient was found to have a SLC20A2 mutation known to be pathogenic in PFBC, as well as a variant of unknown significance in SCN2A. This case demonstrates that the ictal EEG is important for accurately classifying epilepsy in affected subjects with PFBC. Further, epilepsy in PFBC may be a polygenic disorder.
View details for PubMedID 29448117
-
A Small Molecule p75NTR Ligand, LM11A-31, Reverses Cholinergic Neurite Dystrophy in Alzheimer's Disease Mouse Models with Mid- to Late-Stage Disease Progression.
PloS one
2014; 9 (8): e102136
Abstract
Degeneration of basal forebrain cholinergic neurons contributes significantly to the cognitive deficits associated with Alzheimer's disease (AD) and has been attributed to aberrant signaling through the neurotrophin receptor p75 (p75NTR). Thus, modulating p75NTR signaling is considered a promising therapeutic strategy for AD. Accordingly, our laboratory has developed small molecule p75NTR ligands that increase survival signaling and inhibit amyloid-β-induced degenerative signaling in in vitro studies. Previous work found that a lead p75NTR ligand, LM11A-31, prevents degeneration of cholinergic neurites when given to an AD mouse model in the early stages of disease pathology. To extend its potential clinical applications, we sought to determine whether LM11A-31 could reverse cholinergic neurite atrophy when treatment begins in AD mouse models having mid- to late stages of pathology. Reversing pathology may have particular clinical relevance as most AD studies involve patients that are at an advanced pathological stage. In this study, LM11A-31 (50 or 75 mg/kg) was administered orally to two AD mouse models, Thy-1 hAPPLond/Swe (APPL/S) and Tg2576, at age ranges during which marked AD-like pathology manifests. In mid-stage male APPL/S mice, LM11A-31 administered for 3 months starting at 6-8 months of age prevented and/or reversed atrophy of basal forebrain cholinergic neurites and cortical dystrophic neurites. Importantly, a 1 month LM11A-31 treatment given to male APPL/S mice (12-13 months old) with late-stage pathology reversed the degeneration of cholinergic neurites in basal forebrain, ameliorated cortical dystrophic neurites, and normalized increased basal forebrain levels of p75NTR. Similar results were seen in female Tg2576 mice. These findings suggest that LM11A-31 can reduce and/or reverse fundamental AD pathologies in late-stage AD mice. Thus, targeting p75NTR is a promising approach to reducing AD-related degenerative processes that have progressed beyond early stages.
View details for DOI 10.1371/journal.pone.0102136
View details for PubMedID 25153701
View details for PubMedCentralID PMC4143160
-
A small molecule p75NTR ligand, LM11A-31, reverses cholinergic neurite dystrophy in Alzheimer's disease mouse models with mid- to late-stage disease progression.
PloS one
2014; 9 (8)
Abstract
Degeneration of basal forebrain cholinergic neurons contributes significantly to the cognitive deficits associated with Alzheimer's disease (AD) and has been attributed to aberrant signaling through the neurotrophin receptor p75 (p75NTR). Thus, modulating p75NTR signaling is considered a promising therapeutic strategy for AD. Accordingly, our laboratory has developed small molecule p75NTR ligands that increase survival signaling and inhibit amyloid-β-induced degenerative signaling in in vitro studies. Previous work found that a lead p75NTR ligand, LM11A-31, prevents degeneration of cholinergic neurites when given to an AD mouse model in the early stages of disease pathology. To extend its potential clinical applications, we sought to determine whether LM11A-31 could reverse cholinergic neurite atrophy when treatment begins in AD mouse models having mid- to late stages of pathology. Reversing pathology may have particular clinical relevance as most AD studies involve patients that are at an advanced pathological stage. In this study, LM11A-31 (50 or 75 mg/kg) was administered orally to two AD mouse models, Thy-1 hAPPLond/Swe (APPL/S) and Tg2576, at age ranges during which marked AD-like pathology manifests. In mid-stage male APPL/S mice, LM11A-31 administered for 3 months starting at 6-8 months of age prevented and/or reversed atrophy of basal forebrain cholinergic neurites and cortical dystrophic neurites. Importantly, a 1 month LM11A-31 treatment given to male APPL/S mice (12-13 months old) with late-stage pathology reversed the degeneration of cholinergic neurites in basal forebrain, ameliorated cortical dystrophic neurites, and normalized increased basal forebrain levels of p75NTR. Similar results were seen in female Tg2576 mice. These findings suggest that LM11A-31 can reduce and/or reverse fundamental AD pathologies in late-stage AD mice. Thus, targeting p75NTR is a promising approach to reducing AD-related degenerative processes that have progressed beyond early stages.
View details for DOI 10.1371/journal.pone.0102136
View details for PubMedID 25153701
View details for PubMedCentralID PMC4143160
-
A small molecule p75(NTR) ligand prevents cognitive deficits and neurite degeneration in an Alzheimer's mouse model.
Neurobiology of aging
2013; 34 (8): 2052-2063
Abstract
The p75 neurotrophin receptor (p75(NTR)) is associated with multiple mechanisms linked to Alzheimer's disease (AD); hence, modulating its function might confer therapeutic effects. In previous in vitro work, we developed small molecule p75(NTR) ligands that inhibited amyloid-β-induced degenerative signaling and prevented neurite degeneration. In the present study, a prototype p75(NTR) ligand, LM11A-31, was administered orally to the Thy-1 hAPP(Lond/Swe) (APP(L/S)) AD mouse model. LM11A-31 reached brain concentrations known to inhibit degenerative signaling without toxicity or induction of hyperalgesia. It prevented deficits in novel object recognition after 2.5 months and, in a separate cohort, deficits in Y-maze performance after 3 months of treatment. Stereology studies found that the number and size of basal forebrain cholinergic neurons, which are normal in APP(L/S) mice, were unaffected. Neuritic dystrophy, however, was readily apparent in the basal forebrain, hippocampus and cortex, and was significantly reduced by LM11A-31, with no effect on amyloid levels. These studies reveal that p75(NTR) is an important and tractable in vivo drug target for AD, with LM11A-31 representing a novel class of therapeutic candidates.
View details for DOI 10.1016/j.neurobiolaging.2013.02.015
View details for PubMedID 23545424
-
The p75 Neurotrophin Receptor Promotes Amyloid-beta(1-42)-Induced Neuritic Dystrophy In Vitro and In Vivo
JOURNAL OF NEUROSCIENCE
2009; 29 (34): 10627-10637
Abstract
Oligomeric forms of amyloid-beta (Abeta) are thought to play a causal role in Alzheimer's disease (AD), and the p75 neurotrophin receptor (p75(NTR)) has been implicated in Abeta-induced neurodegeneration. To further define the functions of p75(NTR) in AD, we examined the interaction of oligomeric Abeta(1-42) with p75(NTR), and the effects of that interaction on neurite integrity in neuron cultures and in a chronic AD mouse model. Atomic force microscopy was used to ascertain the aggregated state of Abeta, and fluorescence resonance energy transfer analysis revealed that Abeta oligomers interact with the extracellular domain of p75(NTR). In vitro studies of Abeta-induced death in neuron cultures isolated from wild-type and p75(NTR-/-) mice, in which the p75(NTR) extracellular domain is deleted, showed reduced sensitivity of mutant cells to Abeta-induced cell death. Interestingly, Abeta-induced neuritic dystrophy and activation of c-Jun, a known mediator of Abeta-induced deleterious signaling, were completely prevented in p75(NTR-/-) neuron cultures. Thy1-hAPP(Lond/Swe) x p75(NTR-/-) mice exhibited significantly diminished hippocampal neuritic dystrophy and complete reversal of basal forebrain cholinergic neurite degeneration relative to those expressing wild-type p75(NTR). Abeta levels were not affected, suggesting that removal of p75(NTR) extracellular domain reduced the ability of excess Abeta to promote neuritic degeneration. These findings indicate that although p75(NTR) likely does not mediate all Abeta effects, it does play a significant role in enabling Abeta-induced neurodegeneration in vitro and in vivo, establishing p75(NTR) as an important therapeutic target for AD.
View details for DOI 10.1523/JNEUROSCI.0620-09.2009
View details for PubMedID 19710315
-
Small Molecule, Non-Peptide p75(NTR) Ligands Inhibit A beta-Induced Neurodegeneration and Synaptic Impairment
PLOS ONE
2008; 3 (11)
Abstract
The p75 neurotrophin receptor (p75(NTR)) is expressed by neurons particularly vulnerable in Alzheimer's disease (AD). We tested the hypothesis that non-peptide, small molecule p75(NTR) ligands found to promote survival signaling might prevent Abeta-induced degeneration and synaptic dysfunction. These ligands inhibited Abeta-induced neuritic dystrophy, death of cultured neurons and Abeta-induced death of pyramidal neurons in hippocampal slice cultures. Moreover, ligands inhibited Abeta-induced activation of molecules involved in AD pathology including calpain/cdk5, GSK3beta and c-Jun, and tau phosphorylation, and prevented Abeta-induced inactivation of AKT and CREB. Finally, a p75(NTR) ligand blocked Abeta-induced hippocampal LTP impairment. These studies support an extensive intersection between p75(NTR) signaling and Abeta pathogenic mechanisms, and introduce a class of specific small molecule ligands with the unique ability to block multiple fundamental AD-related signaling pathways, reverse synaptic impairment and inhibit Abeta-induced neuronal dystrophy and death.
View details for DOI 10.1371/journal.pone.0003604
View details for Web of Science ID 000265134200003
View details for PubMedID 18978948
View details for PubMedCentralID PMC2575383
-
Small molecule neurotrophin receptor ligands: Novel strategies for targeting Alzheimer's disease mechanisms
7th International Conference on Alzheimers Disease Drug Discovery
BENTHAM SCIENCE PUBL LTD. 2007: 503–6
Abstract
A number of factors limit the therapeutic application of neurotrophin proteins, such as nerve growth factor (NGF) and brain-derived growth factor (BDNF), for Alzheimer's and other neurodegenerative diseases. These factors include unfavorable pharmacological properties typical of proteins and the pleiotropic effects mediated by protein-ligand interactions with p75(NTR), Trk, and sortilin neurotrophin receptors. Targeted modulation of p75(NTR) provides a strategy for preventing degeneration without promoting TrkA-mediated deleterious effects, and targeted activation of TrkB might achieve more favorable neurotrophic effects than those achieved by concomitant activation of p75(NTR) and TrkB. The discovery of small molecules functioning as ligands at specific neurotrophin receptors has made possible for the first time approaches for modulating selected components of neurotrophin signaling processes for the purpose of modulating underlying Alzheimer's disease mechanisms.
View details for Web of Science ID 000253592000002
View details for PubMedID 18220511