New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

HAP1 facilitates effects of mutant huntingtin on inositol 1,4,5-trisphosphate-induced Ca2+ release in primary culture of striatal medium spiny neurons

Huntington's disease is caused by polyglutamine expansion (exp) in huntingtin (Htt). Htt-associated protein-1 (HAP1) was the first identified Htt-binding partner. The type 1 inositol (1,4,5)-trisphosphate receptor (InsP3R1) is an intracellular Ca2+ release channel that plays an important role in neuronal function. Recently, we identified a InsP3R1-HAP1A-Htt ternary complex in the brain and demonstrated that Httexp, but not normal Htt, activates InsP3R1 in bilayers and facilitates InsP3R1-mediated intracellular Ca2+ release in medium spiny striatal neurons [MSN; T.-S. Tang et al. (2003) Neuron, 39, 227-239]. Here we took advantage of mice with targeted disruption of both HAP1 alleles (HAP1 -/-) to investigate the role of HAP1 in functional interactions between Htt and InsP3R1. We determined that: (i) HAP1 is expressed in the MSN; (ii) HAP1A facilitates functional effects of Htt and Htt(exp) on InsP3R1 in planar lipid bilayers; (iii) HAP1 is required for changes in MSN basal Ca2+ levels resulting from Htt or Htt(exp) overexpression; (iv) HAP1 facilitates potentiation of InsP3R1-mediated Ca2+ release by Htt(exp) in mouse MSN. Our present results indicate that HAP1 plays an important role in functional interactions between Htt and InsP3R1

Comparison of the effect of fluosol DA and dextran 40 on regional cerebral blood flow, infarction size, and mortality in cats with temporary occlusion of the middle cerebral artery

Twenty-four cats were divided into two groups and treated with an intravenous infusion of either fluosol DA or dextran. One-half of the animals in each group were ventilated with room air and one-half with 100% oxygen. The right middle cerebral artery was occluded for a period of 4 hours through a transorbital approach. Regional blood flow by the hydrogen clearance method was measured before and after the infusion of fluosol DA or dextran, after oxygenation in the animals on 100% oxygen, three times during the period of ischemia, and after reperfusion. Regional cerebral blood flow increased slightly with the infusion of fluosol or dextran, decreased slightly with hyperoxygenation in the animals so treated, and decreased markedly in the right hemisphere during temporary occlusion of the right middle cerebral artery in all groups. With reperfusion regional flows in the right hemisphere varied considerably, with some animals showing hyperperfusion and others essentially no flow. There was no significant difference in average regional cerebral blood flow between any of the groups. The severity of infarction in all groups was directly related to the decrease in regional cerebral blood flow in the right hemisphere during temporary occlusion. There was also a strong correlation between the regional cerebral blood flow in the right hemisphere after reperfusion and the severity of infarction. In general, the animals showing normal or increased flow after reperfusion had small infarcts and those showing no reflow had large infarcts. Mortality was high in all groups, was not significantly different between any of the groups, and was highly correlated to the size of infarction. In brief, in this study fluosol offered no advantage over dextran, and probably neither agent, in the dose used, offered any protection against cerebral ischemia

Failure of fluosol to influence the incidence of cerebral infarction or mortality in gerbils subjected to temporary carotid occlusion

Three hundred two gerbils were subjected to 2, 4, or 6 hours of temporary occlusion of the right common carotid artery. The animals were divided into four groups. The first two groups were given an infusion of Fluosol DA 20% (20 ml/kg) before arterial occlusion. One of these groups was kept in an environment of 100% oxygen during the time of occlusion and the other group was kept in room air. The two other groups of animals did not receive Fluosol. One of these groups was kept in 100% oxygen and the other group in room air during the time of arterial occlusion. The surviving animals were sacrificed 7 days later, and their brains were examined grossly and microscopically for evidence of cerebral infarction. There was a lesser incidence of early hemiparesis in the two groups treated with Fluosol, as well as in the untreated group that was kept in 100% oxygen. However, the incidence of infarction and the mortality were not significantly different in any of the groups

Brain gene expression correlates with changes in behavior in the R6/1 mouse model of Huntington's disease

Huntington’s disease (HD) is an inherited neurodegeneration that causes a severe progressive illness and early death. Several animal models of the disease have been generated carrying the causativemutation and these have shown that one of the earliest molecular signs of the disease process is a substantial transcriptional deficit.We examined the alterations in brain gene expression in the R6/1 mouse line over the course of the development of phenotypic signs from 18 to 27 weeks. Changes in R6/1 mice were similar to those previously reported in R6/2 mice, and gene ontology analysis shows that pathways related to intracellular and electrical signaling are altered among downregulated genes and lipid biosynthesis and RNA processes among upregulated genes. The R6/1 mice showed deficits in rotarod performance, locomotor activity and exploratory behavior over the time–course. We have correlated the alterations in gene expression with changes in behavior seen in the mice and find that few alterations in gene expression correlate with all behavioral changes but rather that different subsets of the changes are uniquely correlated with one behavior only. This indicates that multiple behavioral tasks assessing different behavioral domains are likely to be necessary in therapeutic trials in mouse models of HD