Focus on Alzheimer's Disease and Related Disorders

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Experimental work in animals has shown that memory formation depends on a cascade of molecular events. Here we show that variability of human memory performance is related to variability in genes encoding proteins of this signaling cascade, including the NMDA and metabotrobic glutamate receptors, adenylyl cyclase, CAMKII, PKA, and PKC. The individual profile of genetic variability in these signaling molecules correlated significantly with episodic memory performance (P < 0.00001). Moreover, functional MRI during memory formation revealed that this genetic profile correlated with activations in memory-related brain regions, including the hippocampus and parahippocampal gyrus. The present study indicates that genetic variability in the human homologues of memory-related signaling molecules contributes to interindividual differences in human memory performance and memory-related brain activations.genes ͉ molecular cascade ͉ learning D uring the last three decades, animal studies in both invertebrates and vertebrates have identified genes and signaling molecules important for memory, including protein kinases and phosphatases and transcription factors (1-5). From this work, it appears that many memory-related molecular mechanisms are conserved across species. However, it is still largely unknown whether these molecular pathways are also involved in human memory. The major reason for the lack of translation of the animal findings to humans is that pharmacological manipulation of many of these signaling molecules in humans is not feasible due to either safety issues or lack of pharmacologic specificity. Recent advances in the identification of genetic polymorphisms in the human genome (6, 7) opened, however, new avenues for the examination of complex phenotypes such as human memory. Specifically, correlating the interindividual phenotypic variability with individual patterns of genetic variability in genes relevant to the phenotype of interest can powerfully detect its underlying molecular pathways (8). In the case of human memory, this approach is particularly promising, because twin studies revealed an Ϸ50% heritability for memory traits (9, 10). In the present study, we used the behavioral genetics approach to investigate the impact of genetic variability in the human homologues of memory-related signaling molecules on episodic memory. Because functional MRI (fMRI) can visualize brain processes involved in early memory formation (11, 12), we used this technique to capture genotype effects on the early phase of episodic memory (i.e., short-term memory) and to validate the genetic findings. In addition to short-term memory-related genes, we also investigated genes implicated in the formation of long-term memory (1-5), because human short-term memory performance is affected by preexisting associative networks stored in long-term memory (13).A total of 336 healthy human subjects underwent an episodic memory task. Subjects viewed six series of five semantically unrelated nouns presented at a rate of one word per second ...

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Identification of a genetic cluster influencing memory performance and hippocampal activity in humans

Quervain

Papassotiropoulos

2006

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153

122

“…Brdt was considered to be specifically expressed in mid-to late spermatocytes (41), but is also expressed during brain development (42). Polymorphisms in Soat1 (ACAT1) have been identified as risk factors in Alzheimer's disease (43). The function of Hars lies in protein biosynthesis; a negative correlation with adult neurogenesis is not very plausible based on the currently available information.…”

Section: Discussionmentioning

confidence: 99%

Natural variation and genetic covariance in adult hippocampal neurogenesis

Kempermann

Chesler

et al. 2006

179

162

Adult hippocampal neurogenesis is highly variable and heritable among laboratory strains of mice. Adult neurogenesis is also remarkably plastic and can be modulated by environment and activity. Here, we provide a systematic quantitative analysis of adult hippocampal neurogenesis in two large genetic reference panels of recombinant inbred strains (BXD and AXB͞BXA, n ‫؍‬ 52 strains). We combined data on variation in neurogenesis with a new transcriptome database to extract a set of 190 genes with expression patterns that are also highly variable and that covary with rates of (i) cell proliferation, (ii) cell survival, or the numbers of surviving (iii) new neurons, and (iv) astrocytes. Expression of a subset of these neurogenesis-associated transcripts was controlled in cis across the BXD set. These self-modulating genes are particularly interesting candidates to control neurogenesis. Among these were musashi (Msi1h) and prominin1͞CD133 (Prom1), both of which are linked to stem-cell maintenance and division. Twelve neurogenesis-associated transcripts had significant cis-acting quantitative trait loci, and, of these, six had plausible biological association with adult neurogenesis (Prom1, Ssbp2, Kcnq2, Ndufs2, Camk4, and Kcnj9). Only one cis-acting candidate was linked to both neurogenesis and gliogenesis, Rapgef6, a downstream target of ras signaling. The use of genetic reference panels coupled with phenotyping and global transcriptome profiling thus allowed insight into the complexity of the genetic control of adult neurogenesis.gene array ͉ hippocampus ͉ precursor ͉ quantitative trait loci ͉ stem cell N eurogenesis in adult mammals is modulated by complex interactions among genetic and environmental factors. Our goal is to use a systems genetics approach to determine how the development of new neurons and glia is modulated by gene polymorphisms, activity, and environmental stimuli. A first step toward this goal is to analyze natural variation and genetic covariance among key neurogenesis parameters such as proliferation, survival, and differentiation of new cells. We have shown that natural variation is substantial among different strains of mice (1-3). The normal range of variation often exceeds the effects of single gene mutations in engineered lines of mice.In this study, we extended this analysis of normal variation and applied a systems genetics approach to study the covariance structure of four key parameters of adult hippocampal neurogenesis across two large genetic reference populations consisting of a total of 52 recombinant inbred strains. This approach allowed us to exploit covariance of diverse traits to demonstrate biological linkage and pleiotropy (4, 5). The analysis, however, extends beyond a correlative approach. Both of the genetic reference populations used, the BXD and AXB͞BXA sets, are standard mapping panels, making it possible to search for gene loci, so-called quantitative trait loci (QTL), that produce common variation and pleiotropy among traits linked to adult hippocampal neurogenesis.A...

“…The Zurich case-control series, the Newcastle Brain Bank (U.K. series), and various brain banks throughout the United States (U.S. series) have been recently described (23,24). The affected sibling pairs (ASPs) sample was provided by the National Institute of Mental Health (NIMH), the National Cell Repository for AD (Grant U24 AG21886) and the United Kingdom.…”

Section: Methodsmentioning

confidence: 99%

Common genetic variation within the Low-Density Lipoprotein Receptor-Related Protein 6 and late-onset Alzheimer's disease

Ferrari

Papassotiropoulos

Biechele

et al. 2007

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259

224

Genome-wide linkage studies have defined a broad susceptibility region for late-onset Alzheimer's disease on chromosome 12, which contains the Low-Density Lipoprotein Receptor-Related Protein 6 (LRP6) gene, a coreceptor for Wnt signaling. Here, we report the association between common LRP6 variants and late-onset Alzheimer's disease in a multicenter case-control series as well as in a large family-based series ascertained by the National Institute of Mental Health-National Institute on Aging Genetics Initiative. As shown in the genome-wide linkage studies, our association depends mainly on apolipoprotein E-4 (APOE-4) carrier status. Haplotype tagging single-nucleotide polymorphisms (SNPs) with a set of seven allelic variants of LRP6 identified a putative risk haplotype, which includes a highly conserved coding sequence SNP: Ile-1062 3 Val. Functional analyses revealed that the associated allele Val-1062, an allele previously linked to low bone mass, has decreased ␤-catenin signaling in HEK293T cells. Our study unveils a genetic relationship between LRP6 and APOE and supports the hypothesis that altered Wnt/␤-catenin signaling may be involved in this neurodegenerative disease.neurodegenerative ͉ LRP-6 ͉ single-nucleotide polymorphism ͉ APOE ͉ Wnt