Category: genotype Project: Pharmacogenetics of Membrane Transporters [Table 1][1] provides HUGO Gene Nomenclature Committee (HGNC) symbols, PharmGKB submission URLs, submission dates, and release dates. [Table 2][2] provides HGNC symbols, HGNC names, synonyms, GenBank accession numbers, and locus

The deficits characteristic of Alzheimer's disease (AD) are believed to result, at least in part, from the neurotoxic effects of beta-amyloid peptides, a set of 39-43 amino acid fragments derived proteolytically from beta-amyloid precursor protein (APP). APP also is cleaved intracytoplasmically at Asp-664 to generate a second cytotoxic peptide, APP-C31, but whether this C-terminal processing of APP plays a role in the pathogenesis of AD is unknown. Therefore, we compared elements of the Alzheimer's phenotype in transgenic mice modeling AD with vs. without a functional Asp-664 caspase cleavage site. Surprisingly, whereas beta-amyloid production and plaque formation were unaltered, synaptic loss, astrogliosis, dentate gyral atrophy, increased neuronal precursor proliferation, and behavioral abnormalities were completely prevented by a mutation at Asp-664. These results suggest that Asp-664 plays a critical role in the generation of Alzheimer-related pathophysiological and behavioral changes in human APP transgenic mice, possibly as a cleavage site or via protein-protein interactions.

The deficits characteristic of Alzheimer's disease (AD) are believed to result, at least in part, from the neurotoxic effects of beta-amyloid peptides, a set of 39-43 amino acid fragments derived proteolytically from beta-amyloid precursor protein (APP). APP also is cleaved intracytoplasmically at Asp-664 to generate a second cytotoxic peptide, APP-C31, but whether this C-terminal processing of APP plays a role in the pathogenesis of AD is unknown. Therefore, we compared elements of the Alzheimer's phenotype in transgenic mice modeling AD with vs. without a functional Asp-664 caspase cleavage site. Surprisingly, whereas beta-amyloid production and plaque formation were unaltered, synaptic loss, astrogliosis, dentate gyral atrophy, increased neuronal precursor proliferation, and behavioral abnormalities were completely prevented by a mutation at Asp-664. These results suggest that Asp-664 plays a critical role in the generation of Alzheimer-related pathophysiological and behavioral changes in human APP transgenic mice, possibly as a cleavage site or via protein-protein interactions.

Category: Genotype PharmGKB Submission Number: PS203001 Date of Submission: June 16, 2003 Project: Pharmacogenetics of Membrane Transporters HGNC Symbol: SLC22A1 HGNC Name: solute carrier family 22 (organic cation transporter), member 1

Activation of postsynaptic N-methyl-D-aspartate (NMDA) receptors followed by excessive Ca 2+ influx into neurons are common mechanisms underlying acute brain insults, such as stroke, hypoglycemia, trauma, and epilepsy; in some cases, they may be responsible for the chronic onset of neurodegenerative diseases. Oxygen-derived free radicals have been demonstrated to be present in the amplification cascades of the overstimulation of neuronal NMDA receptors. Intrastriatal infusion of NMDA (15 nmol/3 μl, 20 min) caused hippocampal neuronal death 3 days later in adult (16 months old) mice. Histologic examinations revealed that the neurons in the CA2, and CA3 subfields are most susceptible (3 of 6 animals) to NMDA toxicity followed by the neurons of the dentate gyrus (2 of 6), and the hippocampal CA 1 (1 of 6) subfield. However, NMDA neurotoxicity was significantly reduced in adult transgenic mice expressing a threefold increase in human CuZn-superoxide dismutase activity. Only 1 of 7 superoxide dismutase transgenic mice exhibited neuronal necrosis in hippocampal CA 1 , CA 2 , CA 3 , and dentate gyrus, as quantified by cresyl violet staining. These data may imply that superoxide radicals are involved in NMDA neurotoxicity in vivo and that overexpression of CuZn-superoxide dismutase activity in neural cells offers neuronal protection against oxidative injury resulting from the overexcitation of NMDA receptors.

The activity of CuZn-superoxide dismutase (CuZnSOD) in the brain and other tissues of mice has been increased between 1.5- and 5-fold by the insertion of one or more human CuZnSOD transgenes into the mouse genome. Although physically normal, these transgenic mice exhibit several differences from control mice when exposed to known or presumed forms of oxidative stress. After a 30-second cold injury to the cerebral cortex, transgenic mice with approximately 3-times normal CuZnSOD activity have less cerebral edema, a smaller increase in vascular permeability, and a smaller area of infarction than do the control animals. These transgenic animals are also protected to a significant degree against the effects of transient focal cerebral ischemia in the middle cerebral artery distribution, with sparing particularly of the penumbra region surrounding the ischemic brain tissue. Furthermore, in contrast to control animals, the injection of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) into transgenic mice does not induce any depletion in striatal levels of dopamine and its metabolites or decreases in dopamine uptake sites. MPTP is an agent which causes changes in the dopaminergic system similar to those observed in Parkinson’s disease. Cultured primary cortical neurons from transgenic fetuses demonstrate a significant reduction in the toxic effects of exposure to 0.5 mM glutamate.

Recently, we have shown that transgenic mice which exhibit increased superoxide dismutase (SOD) activity are resistant to N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. Increased SOD activity has been related to impairment of cell membrane characteristics and enhanced lipid peroxidation. Thus it was thought that resistance to MPTP might possibly be attributable to alteration in the distribution of MPTP which is a highly lipophilic compound. This idea was stimulated by a previous suggestion that the resistance manifested by rats to MPTP might be due to a low level of [3H]-MPTP binding sites in brain regions which are critical to MPTP-induced toxicity. The comparison of the binding of [3H]-MPTP in the brain of SOD-transgenic mice and their nontransgenic littermates did not reveal any significant difference in either brain distribution or in concentrations of [3H]-MPTP binding between the two groups. Our data indicate that the observed lack of MPTP-induced toxicity of SOD-transgenic mice is not related to abnormal binding of the toxin in the brain of these transgenic animals which exhibit 2.07 to 3.48 higher SOD activity than their nontransgenic littermates. In addition, this study provides a normative description of the regional distribution of [3H]-MPTP binding in the brain of normal mice.