Faculty Bibliography
Searched for:
school:SOM
Department/Unit:Neuroscience Institute
Total Results:
13474
Single domain antibodies targeting pathological tau protein: Influence of four IgG subclasses on efficacy and toxicity
BACKGROUND:Eleven tau immunoglobulin G (IgG) antibodies have entered clinical trials to treat tauopathies, including Alzheimer's disease, but it is unclear which IgG subclass/subtype has the ideal efficacy and safety profile. Only two subtypes, with or without effector function, have been examined in the clinic and not for the same tau antibody. The few preclinical studies on this topic have only compared two subtypes of one antibody each and have yielded conflicting results. METHODS:subclasses containing identical tau binding domains but differing Fc region. Unmodified sdAbs and their IgG subclasses were tested for efficacy in primary cultures and in vivo microdialysis using JNPL3 tauopathy mice. FINDINGS/RESULTS:subclasses varied greatly within and between sdAbs. For one of them, all its subtypes were non-toxic, only those with effector function cleared tau, and were more effective in vivo than unmodified sdAb. For the other sdAb, all its subtypes were toxic in tauopathy cultures but not in wild-type cells, suggesting that bivalent binding of its tau epitope stabilizes a toxic conformation of tau, with major implications for tau pathogenesis. Likewise, its subclasses were less effective than the unmodified sdAb in clearing tau in vivo. INTERPRETATION/CONCLUSIONS:These findings indicate that tau antibodies with effector function are safe and better at clearing pathological tau than effectorless antibodies, Furthermore, tau antibodies can provide a valuable insight into tau pathogenesis, and some may aggravate it. FUNDING/BACKGROUND:Funding for these studies was provided by the National Institute of Health (R01 AG032611, R01 NS077239, RF1 NS120488, R21 AG 069475, R21 AG 058282, T32AG052909), and the NYU Alzheimer's Disease Center Pilot Grant Program (via P30 AG008051).
PMCID:9475275
PMID: 36099813
ISSN: 2352-3964
CID: 5332822
Insulin signaling in the long-lived reproductive caste of ants
In most organisms, reproduction is correlated with shorter life span. However, the reproductive queen in eusocial insects exhibits a much longer life span than that of workers. In Harpegnathos ants, when the queen dies, workers can undergo an adult caste switch to reproductive pseudo-queens (gamergates), exhibiting a five-times prolonged life span. To explore the relation between reproduction and longevity, we compared gene expression during caste switching. Insulin expression is increased in the gamergate brain that correlates with increased lipid synthesis and production of vitellogenin in the fat body, both transported to the egg. This results from activation of the mitogen-activated protein kinase (MAPK) branch of the insulin signaling pathway. By contrast, the production in the gamergate developing ovary of anti-insulin Imp-L2 leads to decreased signaling of the AKT/forkhead box O (FOXO) branch in the fat body, which is consistent with their extended longevity.
PMID: 36048960
ISSN: 1095-9203
CID: 5332152
American journal of respiratory & critical care medicine. 2022:206(5):632-636.DOI: 10.1164/rccm.202201-0107LE
Obstructive Sleep Apnea and Hypertension with Longitudinal β-Amyloid Burden and Cognitive Changes
PMID: 35550019
ISSN: 1535-4970
CID: 5213082
An integrative study of the microbiome gut-brain-axis and hippocampal inflammation in psychosis: Persistent effects from mode of birth
The mechanism producing psychosis appears to include hippocampal inflammation, which could be associated with the microbiome-gut-brain-axis (MGBS). To test this hypothesis we are conducting a multidisciplinary study, herein described. The procedures are illustrated with testing of a single subject and group level information on the impact of C-section birth are presented.
PMID: 34625336
ISSN: 1573-2509
CID: 5067852
Publisher Correction: Viral manipulation of functionally distinct interneurons in mice, non-human primates and humans
PMID: 35945454
ISSN: 1546-1726
CID: 5286892
Inhibitory conductance controls place field dynamics in the hippocampus
Hippocampal place cells receive a disparate collection of excitatory and inhibitory currents that endow them with spatially selective discharges and rhythmic activity. Using a combination of in vivo intracellular and extracellular recordings with opto/chemogenetic manipulations and computational modeling, we investigate the influence of inhibitory and excitatory inputs on CA1 pyramidal cell responses. At the cell bodies, inhibition leads and is stronger than excitation across the entire theta cycle. Pyramidal neurons fire on the ascending phase of theta when released from inhibition. Computational models equipped with the observed conductances reproduce these dynamics. In these models, place field properties are favored when the increased excitation is coupled with a reduction of inhibition within the field. As predicted by our simulations, firing rate within place fields and phase locking to theta are impaired by DREADDs activation of interneurons. Our results indicate that decreased inhibitory conductance is critical for place field expression.
PMID: 36001959
ISSN: 2211-1247
CID: 5312472
ATP-binding cassette protein ABCA7 deficiency impairs sphingomyelin synthesis, cognitive discrimination, and synaptic plasticity in the entorhinal cortex
Sphingomyelin (SM) is an abundant plasma membrane and plasma lipoprotein sphingolipid. We previously reported that ATP-binding cassette family A protein 1 (ABCA1) deficiency in humans and mice decreases plasma SM levels. However, overexpression, induction, downregulation, inhibition, and knockdown of ABCA1 in human hepatoma Huh7 cells did not decrease SM efflux. Using unbiased siRNA screening, here, we identified that ABCA7 plays a role in the biosynthesis and efflux of SM without affecting cellular uptake and metabolism. Since loss of function mutations in the ABCA7 gene exhibit strong associations with late-onset Alzheimer's disease across racial groups, we also studied the effects of ABCA7 deficiency in the mouse brain. Brains of ABCA7-deficient (KO) mice, compared with WT, had significantly lower levels of several SM species with long chain fatty acids. In addition, we observed that older KO mice exhibited behavioral deficits in cognitive discrimination in the active place avoidance task. Next, we performed synaptic transmission studies in brain slices obtained from older mice. We found anomalies in synaptic plasticity at the intracortical synapse in layer II/III of the lateral entorhinal cortex but not in the hippocampal CA3-CA1 synapses in KO mice. These synaptic abnormalities in KO brain slices were rescued with extracellular SM supplementation but not by supplementation with phosphatidylcholine. Taken together, these studies identify a role of ABCA7 in brain SM metabolism and the importance of SM in synaptic plasticity and cognition, as well as provide a possible explanation for the association between ABCA7 and late-onset Alzheimer's disease.
PMCID:9513280
PMID: 36007616
ISSN: 1083-351x
CID: 5338452
Responses and functions of dopamine in nucleus accumbens core during social behaviors
Social behaviors are among the most important motivated behaviors. How dopamine (DA), a "reward" signal, releases during social behaviors has been a topic of interest for decades. Here, we use a genetically encoded DA sensor, GRABDA2m, to record DA activity in the nucleus accumbens (NAc) core during various social behaviors in male and female mice. We find that DA releases during approach, investigation and consummation phases of social behaviors signal animals' motivation, familiarity of the social target, and valence of the experience, respectively. Positive and negative social experiences evoke opposite DA patterns. Furthermore, DA releases during mating and fighting are sexually dimorphic with a higher level in males than in females. At the functional level, increasing DA in NAc enhances social interest toward a familiar conspecific and alleviates defeat-induced social avoidance. Altogether, our results reveal complex information encoded by NAc DA activity during social behaviors and their multistage functional roles.
PMID: 36001967
ISSN: 2211-1247
CID: 5312482
Virtual Ontogeny of Cortical Growth Preceding Mental Illness
BACKGROUND:Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life. METHODS:Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed. RESULTS:Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth. CONCLUSIONS:Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy.
PMID: 35489875
ISSN: 1873-2402
CID: 5217792
Preemptive Removal of Small, Asymptomatic Kidney Stones [Editorial]
PMID: 35947713
ISSN: 1533-4406
CID: 5286962
