This proposal aims to genetically determine the involvement of excess N-methyl-D-aspartate receptor (NMDAR) activity in the pathogenesis of early cognitive deficits of Down syndrome. Oligomeric Ap peptides are known to be generated very early in Down syndrome because of the extra copy of the APP (amyloid precursor protein) gene on chromosome 21 (the trisomic chromosome in humans with Down syndrome). We propose that the early synaptic damage that is known to occur in Down syndrome brains may, at least in part, be due to excessive levels of Ap peptides. One possible mechanism by which excessive AB may cause synaptic loss and neuronal injury is via NMDAR activation, since it is known that AB increases glutamate release from astrocytes. NR3A subunits inhibit NMDAR activity and act as neuroprotective molecules that mitigate neuronal injury caused by various experimental paradigms. Our recent data indicate that AB induces greater synaptic injury to NR3A-knockout (KO) neurons compared to wild-type (WT) neurons. In addition, we have identified a large gene family that we named takusan (meaning "many" in Japanese), which regulates synaptic activity. Based on the properties of takusan proteins, we postulated that this molecule might also protect synapses. In this proposal, we will genetically cross Ts65Dn mice, a mouse model of Down syndrome, with mice mutant in NR3A or takusan genes. We will then evaluate the consequences of these crosses for early neurological and cognitive deficits, as well as dendritic spine loss and electrophysiological abnormalities that have been observed in Ts65Dn mice. These experiments will determine whether NR3A and/or takusan play mechanistic roles in possible protection from the synaptic damage that occurs in Down syndrome.
Our Specific Aims are as follows: (1) To determine the potential ill effect of NRSA KO of the NMDAR in the pathogenesis of cognitive deficits in Down syndrome. (2) To determine the potential beneficial effect of expression of the NR3A subunit of the NMDAR on the pathogenesis of cognitive deficits in Down syndrome. (3) To identify the effect of takusan in protecting from AB-induced synaptic spine loss.
The incidence of Down syndrome in the US population is rising as maternal age increases, in spite of improved screenings. The quality of life for those with Down syndrome is most affected by intellectual and neurological disabilities. This proposal aims to understand the pathogenesis of early cognitive deficits in Down syndrome, so that rational and effective therapies can be developed.
|Akhtar, Mohd Waseem; Sanz-Blasco, Sara; Dolatabadi, Nima et al. (2016) Elevated glucose and oligomeric Î²-amyloid disrupt synapses via a common pathway of aberrant protein S-nitrosylation. Nat Commun 7:10242|
|Nakamura, Tomohiro; Lipton, Stuart A (2016) Protein S-Nitrosylation as a Therapeutic Target for Neurodegenerative Diseases. Trends Pharmacol Sci 37:73-84|
|Nakanishi, Nobuki; Kang, Yeon-Joo; Tu, Shichun et al. (2016) Differential Effects of Pharmacologic and Genetic Modulation of NMDA Receptor Activity on HIV/gp120-Induced Neuronal Damage in an In Vivo Mouse Model. J Mol Neurosci 58:59-65|
|Sanz-Blasco, Sara; PiÃ±a-Crespo, Juan C; Zhang, Xiaofei et al. (2016) Levetiracetam inhibits oligomeric AÎ²-induced glutamate release from human astrocytes. Neuroreport 27:705-9|
|Nakamura, Tomohiro; Lipton, Stuart A (2016) Nitrosative Stress in the Nervous System: Guidelines for Designing Experimental Strategies to Study Protein S-Nitrosylation. Neurochem Res 41:510-4|
|Sunico, Carmen R; Sultan, Abdullah; Nakamura, Tomohiro et al. (2016) Role of sulfiredoxin as a peroxiredoxin-2 denitrosylase in human iPSC-derived dopaminergic neurons. Proc Natl Acad Sci U S A 113:E7564-E7571|
|Nakamura, Tomohiro; Prikhodko, Olga A; Pirie, Elaine et al. (2015) Aberrant protein S-nitrosylation contributes to the pathophysiology of neurodegenerative diseases. Neurobiol Dis 84:99-108|
|Satoh, Takumi; Stalder, Romain; McKercher, Scott R et al. (2015) Nrf2 and HSF-1 Pathway Activation via Hydroquinone-Based Proelectrophilic Small Molecules is Regulated by Electrochemical Oxidation Potential. ASN Neuro 7:|
|Galluzzi, L; Bravo-San Pedro, J M; Vitale, I et al. (2015) Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ 22:58-73|
|Zhang, Dongxian; Lee, Brian; Nutter, Anthony et al. (2015) Protection from cyanide-induced brain injury by the Nrf2 transcriptional activator carnosic acid. J Neurochem 133:898-908|
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