New York State Institute for Basic Research in Developmental Disabilities

New York City, NY, United States

New York State Institute for Basic Research in Developmental Disabilities

New York City, NY, United States

Time filter

Source Type

Chen J.,Shanghai JiaoTong University | Alberts I.,City University of New York | Li X.,New York State Institute for Basic Research in Developmental Disabilities
International Journal of Developmental Neuroscience | Year: 2014

The IGF-I/PI3K/AKT/mTOR signaling pathway plays an important role in the regulation of cell growth, proliferation, differentiation, motility, survival, metabolism and protein synthesis. Insulin-like growth factor-I (IGF-I) is synthesized in the liver and fibroblasts, and its biological actions are mediated by the IGF-I receptor (IGF-IR). The binding of IGF-I to IGF-IR leads to the activation of phosphatidylinositol 3-kinase (PI3K). Activated PI3K stimulates the production of phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2] and phosphatidylinositol (3,4,5)-trisphosphate [PI(3,4,5)P3]. The PH domain of AKT (protein kinase B, PKB) (v-AKT murine thymoma viral oncogene homolog) binds to PI(4,5)P2 and PI(3,4,5)P3, followed by phosphorylation of the Thr308 and Ser473 regulatory sites. Tuberous sclerosis complex 1 (TSC1) and TSC2 are upstream regulators of mammalian target of rapamycin (mTOR) and downstream effectors of the PI3K/AKT signaling pathway. The activation of AKT suppresses the TSC1/TSC2 heterodimer, which is an upstream regulator of mTOR. Dysregulated IGF-I/PI3K/AKT/mTOR signaling has been shown to be associated with autism spectrum disorders (ASDs). In this review, we discuss the emerging evidence for a functional relationship between the IGF-I/PI3K/AKT/mTOR pathway and ASDs, as well as a possible role of this signaling pathway in the diagnosis and treatment of ASDs. © 2014 ISDN.


News Article | November 25, 2015
Site: www.biosciencetechnology.com

The risk of Alzheimer’s disease—the most common cause of dementia—increases as a person ages. But the risk of Alzheimer’s is increased dramatically for adults with Down syndrome. At age 40, individuals with Down syndrome already have the neuropathological changes of Alzheimer’s disease, including the telltale buildup of amyloid plaques and tau tangles that precede symptoms. The early buildup occurs because people with Down syndrome carry an extra copy of chromosome 21, which contains a gene that produces a protein that is a precursor for amyloid. Ninety percent of individuals with Down syndrome will have developed Alzheimer’s disease by age 70 (in the general population, 11 percent of people over age 65 and 32 percent of people over age 85 have Alzheimer’s). However, there is wide variation in age at onset of dementia, ranging from under 40 to over 70 years of age, suggesting that additional genetic, biological, and environmental factors may be important modifiers of risk that accelerate or slow disease progression. New studies at Columbia are designed to explain why some people with Down syndrome develop Alzheimer’s disease earlier than others and why some people with Down syndrome may never develop the disease. With funding from the NIH, Nicole Schupf, Ph.D., DrPH, will identify biomarkers for Alzheimer’s disease in people with Down syndrome, which may help researchers predict who will develop Alzheimer’s in all groups of people. Dr. Schupf is professor of epidemiology at CUMC in Columbia’s Taub Institute for Research on Alzheimer’s Disease and the Aging Brain and the Departments of Neurology and Psychiatry. Many researchers believe that future Alzheimer’s disease treatments may be most effective in the early stages of the disease, before the onset of symptoms and before irreversible neuron loss has occurred. Dr. Schupf’s work will identify biomarkers that can predict the risk of developing Alzheimer’s disease in people with Down syndrome with no symptoms of the degenerative disease. The study focuses on a longitudinal and multidisciplinary determination of key biomarkers that are likely to define the progression from normal aging to onset of dementia, including levels and rates of change in blood-based biomarkers such as b-amyloid peptides, protein, inflammatory and lipid profiles, measures of amyloid and tau concentration in cerebrospinal fluid, neuroimaging-based changes, PET studies of brain amyloid uptake, and genetic polymorphisms. These biomarkers will be combined to develop the most valid indicators of preclinical and early stages of Alzheimer’s. The goal is to develop a noninvasive test to detect Alzheimer’s disease in individuals with Down syndrome and in the broader population. The grant for this prospective study is part of an NIH initiative, Biomarkers of Alzheimer’s Disease in Adults with Down Syndrome, that supports two collaborative teams seeking Alzheimer’s Disease biomarkers in people with Down syndrome. Dr. Schupf leads a team of investigators from Columbia University Medical Center, the University of California, Irvine, Kennedy Krieger Institute/Johns Hopkins University, Massachusetts General Hospital/Harvard, the New York State Institute for Basic Research in Developmental Disabilities, and the University of North Texas Health Sciences Center. The second team is headed by Benjamin Handen, PhD, from the University of Pittsburgh. The two projects will share $37 million in funding over the next five years.


Zhao Y.,Jilin University | Zhao Y.,New York State Institute for Basic Research in Developmental Disabilities | Gong C.-X.,New York State Institute for Basic Research in Developmental Disabilities
Cellular and Molecular Neurobiology | Year: 2014

Chronic cerebral hypoperfusion (CCH) is a common consequence of various cerebral vascular disorders and hemodynamic and blood changes. Recent studies have revealed an important role of CCH in neurodegeneration and dementia, including vascular dementia and Alzheimer’s disease (AD). This article reviews the recent advances in understanding CCH-induced neurodegeneration and AD-related brain pathology and cognitive impairment. We discuss the causes and assessment of CCH, the possible mechanisms by which CCH promotes Alzheimer-like pathology and neurodegeneration, and animal models of CCH. It appears that CCH promotes neurodegeneration and AD through multiple mechanisms, including induction of oxidative stress, Aβ accumulation and aggravation, tau hyperphosphorylation, synaptic dysfunction, neuronal loss, white matter lesion, and neuroinflammation. Better understanding of the mechanisms of CCH will help develop therapeutic strategies for preventing and treating neurodegeneration, including sporadic AD and vascular dementia, caused by CCH. © 2014, Springer Science+Business Media New York.


Oh J.-M.,Hallym University | Choi E.-K.,Hallym University | Carp R.I.,New York State Institute for Basic Research in Developmental Disabilities | Kim Y.-S.,Hallym University
Autophagy | Year: 2012

We previously reported that autophagy is upregulated in Prnp -deficient (Prnp0/0) hippocampal neuronal cells in comparison to cellular prion protein (PrPC)-expressing (Prnp+/+) control cells under conditions of serum deprivation. In this study, we determined whether a protective mechanism of PrPC is associated with autophagy using Prnp 0/0 hippocampal neuronal cells under hydrogen peroxide (H 2O2)-induced oxidative stress. We found that Prnp 0/0 cells were more susceptible to oxidative stress than Prnp +/+ cells in a dose- and time-dependent manner. In addition, we observed enhanced autophagy by immunoblotting, which detected the conversion of microtubule-associated protein 1 light chain 3 β (LC3B)-I to LC3B-II, and we observed increased punctate LC3B immunostaining in H2O 2-treated Prnp0/0 cells compared with H2O 2-treated control cells. Interestingly, this enhanced autophagy was due to impaired autophagic flux in the H2O2-treated Prnp0/0 cells, while the H2O2-treated Prnp+/+ cells showed enhanced autophagic flux. Furthermore, caspase-dependent and independent apoptosis was observed when both cell lines were exposed to H 2O2. Moreover, the inhibition of autophagosome formation by Atg7 siRNA revealed that increased autophagic flux in Prnp+/+ cells contributes to the prosurvival effect of autophagy against H 2O2 cytotoxicity. Taken together, our results provide the first experimental evidence that the deficiency of PrPC may impair autophagic flux via H2O2-induced oxidative stress. © 2012 Landes Bioscience.


Qian W.,Nantong University | Liu F.,Nantong University | Liu F.,New York State Institute for Basic Research in Developmental Disabilities
Neuroscience Bulletin | Year: 2014

The neuronal microtubule-associated protein tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles in the brains of individuals with Alzheimer's disease and related neurodegenerative disorders. The adult human brain expresses six isoforms of tau generated by alternative splicing of exons 2, 3, and 10 of its pre-mRNA. Exon 10 encodes the second microtubule-binding repeat of tau. Its alternative splicing produces tau isoforms with either three or four microtubule-binding repeats, termed 3R-tau and 4Rtau. In the normal adult human brain, the level of 3R-tau is approximately equal to that of 4R-tau. Several silent and intronic mutations of the tau gene associated with FTDP-17T (frontotemporal dementia with Parkinsonism linked to chromosome 17 and specifically characterized by tau pathology) only disrupt exon 10 splicing, but do not influence the primary sequence of the tau protein. Thus, abnormal exon 10 splicing is sufficient to cause neurodegeneration and dementia. Here, we review the regulation of tau exon 10 splicing by cis-elements and trans-factors and summarize all the mutations associated with FTDP-17T and related tauopathies. The findings suggest that correction of exon 10 splicing may be a potential target for tau exon 10 splicing-related tauopathies. © 2014 Shanghai Institutes for Biological Sciences, CAS and Springer-Verlag.


Krinsky-McHale S.J.,New York State Institute for Basic Research in Developmental Disabilities | Silverman W.,Kennedy Krieger Institute
Developmental Disabilities Research Reviews | Year: 2013

Individuals with intellectual disability (ID) are now living longer with the majority of individuals reaching middle and even "old age." As a consequence of this extended longevity they are vulnerable to the same ageassociated health problems as elderly adults in the general population without ID. This includes dementia, a general term referring to a variety of diseases and conditions causing substantial loss of cognitive ability and functional declines; adults with Down syndrome are at especially high risk. A great deal of recent effort has focused on the very earliest detectable indicators of decline (and even prodromal stages of dementiacausing diseases). A condition called mild cognitive impairment (MCI) has been conceptually defined as a decline in functioning that is more severe than expected with typical brain aging but not severe enough to meet criteria for a diagnosis of dementia. Consensus criteria for both dementia and MCI have been developed for typically developing adults but are of limited applicability for adults with ID, given their pre-existing cognitive impairments. Early diagnosis will continue to be of growing importance, both to support symptomatic treatment and to prevent irreversible neuropathology when interventions are developed to slow or halt the progression of underlying disease. While the intellectual and developmental disabilities field has for some time recognized the need to develop bestpractices for the diagnosis of MCI and dementia, there remains a pressing need for empirically based assessment methods and classification criteria. © 2013 Wiley Periodicals, Inc.


Iqbal K.,New York State Institute for Basic Research in Developmental Disabilities | Grundke-Iqbal I.,New York State Institute for Basic Research in Developmental Disabilities
Alzheimer's and Dementia | Year: 2010

Alzheimer's disease (AD) is multifactorial and apparently involves several different etiopathogenic mechanisms. There are at least five subgroups of AD based on cerebrospinal fluid levels of Aβ1-42, a marker of beta-amyloid (Aβ) plaques, and tau and ubiquitin, two markers of neurofibrillary tangles. These different AD subgroups may respond differently to a given disease-modifying drug, and hence, different therapeutic drugs for different disease subgroups might be required. Stratification of AD patients by disease subgroups in clinical trials is critical to the successful development of potent disease-modifying drugs. Levels of disease markers in the cerebrospinal fluid are promising, both in identifying various subgroups of AD and in monitoring the response to therapeutic drugs. © 2010 The Alzheimers Association. All rights reserved.


Wei H.,New York State Institute for Basic Research in Developmental Disabilities
PloS one | Year: 2012

Although the pathogenic mechanisms that underlie autism are not well understood, there is evidence showing that metabotropic and ionotropic glutamate receptors are hyper-stimulated and the GABAergic system is hypo-stimulated in autism. Memantine is an uncompetitive antagonist of NMDA receptors and is widely prescribed for treatment of Alzheimer's disease treatment. Recently, it has been shown to improve language function, social behavior, and self-stimulatory behaviors of some autistic subjects. However the mechanism by which memantine exerts its effect remains to be elucidated. In this study, we used cultured cerebellar granule cells (CGCs) from Fmr1 knockout (KO) mice, a mouse model for fragile X syndrome (FXS) and syndromic autism, to examine the effects of memantine on dendritic spine development and synapse formation. Our results show that the maturation of dendritic spines is delayed in Fmr1-KO CGCs. We also detected reduced excitatory synapse formation in Fmr1-KO CGCs. Memantine treatment of Fmr1-KO CGCs promoted cell adhesion properties. Memantine also stimulated the development of mushroom-shaped mature dendritic spines and restored dendritic spine to normal levels in Fmr1-KO CGCs. Furthermore, we demonstrated that memantine treatment promoted synapse formation and restored the excitatory synapses to a normal range in Fmr1-KO CGCs. These findings suggest that memantine may exert its therapeutic capacity through a stimulatory effect on dendritic spine maturation and excitatory synapse formation, as well as promoting adhesion of CGCs.


Isaacs C.E.,New York State Institute for Basic Research in Developmental Disabilities | Xu W.,New York State Institute for Basic Research in Developmental Disabilities
Antimicrobial Agents and Chemotherapy | Year: 2013

The present study examined the efficacy of using multiple mechanisms as part of a topical microbicide to inactivate herpes simplex virus (HSV) by combining theaflavin-3,3=-digallate (TF-3) and lactic acid (LA) over the pH range of 4.0 to 5.7 to mimic conditions in the female reproductive tract. Six clinical isolates of HSV-2 and two clinical isolates of HSV-1 were almost completely inactivated when TF-3 (100 M) was present with LA over the pH range of 4.5 to 5.7, whereas four additional HSV-1 clinical isolates required TF-3 concentrations of 250 to 500 Mfor comparable virus titer reduction. LA (1%) alone at pH 4.0 reduced the titers of laboratory and clinical isolates of HSV-1 and HSV-2 by>5 log10, but most LA-dependent antiviral activity was lost at a pH of>4.5. When HSV-1 and HSV-2 were incubated at pH 4.0 without LA virus titers were not reduced. At pH 4.0, HSV-1 and HSV-2 titers were reduced 5 log10 in 20 min by LA alone. TF-3 reduced HSV-2 titers by 5 log10 in 20 to 30 min at pH 4.5, whereas HSV-1 required 60 min for comparable inactivation. Mixtures of TF-3 and LA stored at 37C for 1 month at pH 4.0 to 5.7 maintained antiviral activity. Semen, but not cervical vaginal fluid, decreased LA-dependent antiviral activity at pH 4.0, but adding TF-3 to the mixture reduced HSV titers by 4 to 5 log10. These results indicate that a combination microbicide containing TF-3 and LA could reduce HSV transmission. Copyright © 2013, American Society for Microbiology. All Rights Reserved.


Chen Y.,New York State Institute for Basic Research in Developmental Disabilities
Molecular neurobiology | Year: 2013

Alzheimer's disease (AD) can be divided into sporadic AD (SAD) and familial AD (FAD). Most AD cases are sporadic and result from multiple etiologic factors, including environmental, genetic, and metabolic factors, whereas FAD is caused by mutations in the presenilins or amyloid-β (Aβ) precursor protein (APP) genes. A commonly used animal model for AD is the 3xTg-AD transgenic mouse model, which harbors mutated presenilin 1, APP, and tau genes and thus represents a model of FAD. There is an unmet need in the field to characterize animal models representing different AD mechanisms, so that potential drugs for SAD can be evaluated preclinically in these animal models. A mouse model generated by intracerebroventricular (icv) administration of streptozocin (STZ), the icv-STZ mouse, shows many aspects of SAD. In this study, we compared the non-cognitive and cognitive behaviors as well as biochemical and immunohistochemical alterations between the icv-STZ mouse and the 3xTg-AD mouse. We found that both mouse models showed increased exploratory activity as well as impaired learning and spatial memory. Both models also demonstrated neuroinflammation, altered synaptic proteins and insulin/IGF-1 (insulin-like growth factor-1) signaling, and increased hyperphosphorylated tau in the brain. The most prominent brain abnormality in the icv-STZ mouse was neuroinflammation, and in the 3xTg-AD mouse it was elevation of hyperphosphorylated tau. These observations demonstrate the behavioral and neuropathological similarities and differences between the icv-STZ mouse and the 3xTg-AD mouse models and will help guide future studies using these two mouse models for the development of AD drugs.

Loading New York State Institute for Basic Research in Developmental Disabilities collaborators
Loading New York State Institute for Basic Research in Developmental Disabilities collaborators