A novel Alzheimer disease locus located near the gene encoding tau protein.

APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 × 10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.

alpha 1d Adrenoceptor signaling is required for stimulus induced locomotor activity.

alpha 1 Adrenergic receptors mediate a variety of physiological responses and have been well studied in the cardiovascular and peripheral nervous system. However, their role in the central nervous system remains ill defined because of the lack of highly specific ligands to the alpha1 receptor subtypes. Here, we have employed gene targeting to elucidate the role of alpha 1d receptors in vivo. In addition to disrupting function, the insertion of the lacZ gene into the alpha 1d receptor locus enabled the specific identification of cells expressing the alpha 1d gene. These cells are localized in the cortex, hippocampus, olfactory bulb, dorsal geniculate and ventral posterolateral nuclei of the thalamus. Behaviorally, the alpha 1d(-/-) mice show normal locomotor activity during the subjective day, or resting phase of their cycle. However, during subjective night, or active phase, wheel-running activity is significantly reduced in mutant mice. Furthermore, these mice show a reduction in exploratory rearing behavior in a novel cage environment. Lastly, alpha 1d(-/-) mice show reduced hyperlocomotion after acute amphetamine administration. Together, these data reveal the functional importance of alpha 1d adrenoceptors in mediating a variety of stimulus-induced changes in locomotor behaviors. While the sensitivity of noradrenergic neurons to environmental stimuli has been well documented, our data demonstrate that at least some of these post-synaptic responses are mediated by alpha 1d adrenergic receptors.

A role for AMP-activated protein kinase in contraction- and hypoxia-regulated glucose transport in skeletal muscle.

Eukaryotic cells possess systems for sensing nutritional stress and inducing compensatory mechanisms that minimize the consumption of ATP while utilizing alternative energy sources. Such stress can also be imposed by increased energy needs, such as in skeletal muscle of exercising animals. In these studies, we consider the role of the metabolic sensor, AMP-activated protein kinase (AMPK), in the regulation of glucose transport in skeletal muscle. Expression in mouse muscle of a dominant inhibitory mutant of AMPK completely blocked the ability of hypoxia or AICAR to activate hexose uptake, while only partially reducing contraction-stimulated hexose uptake. These data indicate that AMPK transmits a portion of the signal by which muscle contraction increases glucose uptake, but other AMPK-independent pathways also contribute to the response.

An automated system for recording and analysis of sleep in mice.

Significant differences in many aspects of sleep/wake activity among inbred strains of mice suggest genetic influences on the control of sleep. A number of genetic techniques, including transgenesis, random and targeted mutagenesis, and analysis of quantitative trait loci may be used to identify genetic loci. To take full advantage of these genetic approaches in mice, a comprehensive and robust description of behavioral states has been developed. An existing automated sleep scoring algorithm, designed for sleep analysis in rats, has been examined for acceptability in the analysis of baseline sleep structure and the response to sleep deprivation in mice. This algorithm was validated in three inbred strains (C57BL/6J, C3HeB/FeJ, 129X1/SvJ) and one hybrid line (C57BL/6J X C3HeB/FeJ). Overall accuracy rates for behavioral state detection (mean+/-SE) using this system in mice were: waking, 98.8%+/-0.4; NREM sleep, 97.1%+/-0.5; and REM sleep, 89.7%+/-1.4. Characterization of sleep has been extended to include measurements of sleep consolidation and fragmentation, REM sleep latency, and delta density decline with sleep. An experimental protocol is suggested for acquiring baseline sleep data for genetic studies. This sleep recording protocol, scoring, and analysis system is designed to facilitate the understanding of genetic basis of sleep structure.