| 1. |
- Abramsson, Alexandra, 1973, et al.
(författare)
-
The zebrafish amyloid precursor protein-b is required for motor neuron guidance and synapse formation.
- 2013
-
Ingår i: Developmental biology. - : Elsevier BV. - 1095-564X .- 0012-1606. ; 381:2, s. 377-88
-
Tidskriftsartikel (refereegranskat)abstract
- The amyloid precursor protein (APP) is a transmembrane protein mostly recognized for its association with Alzheimer's disease. The physiological function of APP is still not completely understood much because of the redundancy between genes in the APP family. In this study we have used zebrafish to study the physiological function of the zebrafish APP homologue, appb, during development. We show that appb is expressed in post-mitotic neurons in the spinal cord. Knockdown of appb by 50-60% results in a behavioral phenotype with increased spontaneous coiling and prolonged touch-induced activity. The spinal cord motor neurons in these embryos show defective formation and axonal outgrowth patterning. Reduction in Appb also results in patterning defects and changed density of pre- and post-synapses in the neuromuscular junctions. Together, our data show that development of functional locomotion in zebrafish depends on a critical role of Appb in the patterning of motor neurons and neuromuscular junctions.
|
|
| 2. |
- Andersson, Carl-Henrik, et al.
(författare)
-
A Genetic Variant of the Sortilin 1 Gene isAssociated with Reduced Risk ofAlzheimer's Disease
- 2016
-
Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 53:4, s. 1353-1363
-
Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is a neurodegenerative disorder represented by the accumulation of intracellular tau protein and extracellular deposits of amyloid-β (Aβ) in the brain. The gene sortilin 1 (SORT1) has previously been associated with cardiovascular disease in gene association studies. It has also been proposed to be involved in AD pathogenesis through facilitating Aβ clearance by binding apoE/Aβ complexes prior to cellular uptake. However, the neuropathological role of SORT1 in AD is not fully understood. To evaluate the associations between gene variants of SORT1 and risk of AD, we performed genetic analyses in a Swedish case-control cohort. Ten single nucleotide polymorphisms (SNPs), covering the whole SORT1 gene, were selected and genotyped in 620 AD patients and 1107 controls. The SNP rs17646665, located in a non-coding region of the SORT1 gene, remained significantly associated with decreased risk of AD after multiple testing (pc=0.0061). In addition, other SNPs were found to be nominally associated with risk of AD, as well as altered cognitive function and the CSF biomarker Aβ42, but these associations did not survive correction for multiple testing. The fact that SORT1 has been strongly associated with risk of cardiovascular disease is intriguing as cardiovascular disease is also regarded as a risk factor for AD. Finally, increased knowledge about SORT1 function has a potential to increase our understanding of APOE, the strongest risk factor for AD.
|
|
| 3. |
- Bos, I., et al.
(författare)
-
Amyloid-beta, Tau, and Cognition in Cognitively Normal Older Individuals: Examining the Necessity to Adjust for Biomarker Status in Normative Data
- 2018
-
Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 10
-
Tidskriftsartikel (refereegranskat)abstract
- We investigated whether amyloid-beta (A beta) and tau affected cognition in cognitively normal (CN) individuals, and whether norms for neuropsychological tests based on biomarker-negative individuals would improve early detection of dementia. We included 907 CN individuals from 8 European cohorts and from the Alzheimer's disease Neuroimaging Initiative. All individuals were aged above 40, had A beta status and neuropsychological data available. Linear mixed models were used to assess the associations of Ali and tau with five neuropsychological tests assessing memory (immediate and delayed recall of Auditory Verbal Learning Test, AVLT), verbal fluency (Verbal Fluency Test, VFT), attention and executive functioning (Trail Making Test, TMT, part A and B). All test except the VFT were associated with status and this influence was augmented by age. We found no influence of tau on any of the cognitive tests. For the AVLT Immediate and Delayed recall and the TMT part A and B, we calculated norms in individuals without A beta pathology (A beta- norms), which we validated in an independent memory-clinic cohort by comparing their predictive accuracy to published norms. For memory tests, the A beta- norms rightfully identified an additional group of individuals at risk of dementia. For non-memory test we found no difference. We confirmed the relationship between Ao and cognition in cognitively normal individuals. The Af3- norms for memory tests in combination with published norms improve prognostic accuracy of dementia.
|
|
| 4. |
- Hong, Shengjun, et al.
(författare)
-
Genome-wide association study of Alzheimer's disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset.
- 2020
-
Ingår i: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case-control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures derived from quantifications of five separate amyloid-beta (Aβ) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to Aβ42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-Aβ38 and CSF-Aβ40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case-control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-Aβ and -tau-related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.
|
|
| 5. |
- Kettunen, Petronella, et al.
(författare)
-
Calcium imaging in the zebrafish.
- 2012
-
Ingår i: Calcium Signaling. Advances in Experimental Medicine and Biology, Vol. 740, Ed. Shahidul Islam. - Dordrecht : Springer. - 0065-2598. - 9789400728875 ; 740, s. 1039-71
-
Bokkapitel (refereegranskat)abstract
- The zebrafish (Danio rerio) has emerged as a new model system during the last three decades. The fact that the zebrafish larva is transparent enables sophisticated in vivo imaging. While being the vertebrate, the reduced complexity of its nervous system and small size make it possible to follow large-scale activity in the whole brain. Its genome is sequenced and many genetic and molecular tools have been developed that simplify the study of gene function. Since the mid 1990s, the embryonic development and neuronal function of the larval, and later, adult zebrafish have been studied using calcium imaging methods. The choice of calcium indicator depends on the desired number of cells to study and cell accessibility. Dextran indicators have been used to label cells in the developing embryo from dye injection into the one-cell stage. Dextrans have also been useful for retrograde labeling of spinal cord neurons and cells in the olfactory system. Acetoxymethyl (AM) esters permit labeling of larger areas of tissue such as the tectum, a region responsible for visual processing. Genetically encoded calcium indicators have been expressed in various tissues by the use of cell-specific promoters. These studies have contributed greatly to our understanding of basic biological principles during development and adulthood, and of the function of disease-related genes in a vertebrate system.
|
|
| 6. |
- Kettunen, Petronella, et al.
(författare)
-
Calcium Imaging in the Zebrafish.
- 2020
-
Ingår i: Calcium Signaling. Advances in experimental medicine and biology. Islam M. (red.). - Cham : Springer. - 0065-2598. - 9783030124564 ; , s. 901-942
-
Bokkapitel (refereegranskat)abstract
- The zebrafish (Danio rerio) has emerged as a widely used model system during the last four decades. The fact that the zebrafish larva is transparent enables sophisticated in vivo imaging, including calcium imaging of intracellular transients in many different tissues. While being a vertebrate, the reduced complexity of its nervous system and small size make it possible to follow large-scale activity in the whole brain. Its genome is sequenced and many genetic and molecular tools have been developed that simplify the study of gene function in health and disease. Since the mid 90's, the development and neuronal function of the embryonic, larval, and later, adult zebrafish have been studied using calcium imaging methods. This updated chapter is reviewing the advances in methods and research findings of zebrafish calcium imaging during the last decade. The choice of calcium indicator depends on the desired number of cells to study and cell accessibility. Synthetic calcium indicators, conjugated to dextrans and acetoxymethyl (AM) esters, are still used to label specific neuronal cell types in the hindbrain and the olfactory system. However, genetically encoded calcium indicators, such as aequorin and the GCaMP family of indicators, expressed in various tissues by the use of cell-specific promoters, are now the choice for most applications, including brain-wide imaging. Calcium imaging in the zebrafish has contributed greatly to our understanding of basic biological principles during development and adulthood, and the function of disease-related genes in a vertebrate system.
|
|
| 7. |
- Kettunen, Petronella
(författare)
-
Neuromodulation within a spinal locomotor network : role of metabotropic glutamate receptor subtypes
- 2004
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The metabotropic glutamate receptors, mGluRs, are G-protein coupled receptors. They consist of eight cloned subtypes, which are divided into three groups depending on the amino acid sequence similarity, pharmacology and their signal pathways. In the lamprey spinal cord, group I mGluRs are located postsynaptically, while group II and III are presynaptic and depress synaptic transmission. The goal of this thesis has been to elucidate the mechanisms by which the two subtypes of group I mGluRs, i.e. mGluR1 and mGluR5, modulate the firing properties of single neurons, the synaptic interactions and the overall activity of the spinal locomotor network in the lamprey. mGluR1 activation by endogenously released glutamate increases the frequency of the locomotor rhythm induced by NMDA in the isolated lamprey spinal cord preparation. This increase in the frequency is the result of a number of cellular and molecular mechanisms that have been studied in detail. Firstly, mGIuR1 potentiates the NMDA-induced current and modulates NMDAinduced TTX-resistant membrane potential oscillations known to occur during locomotion. Mathematical simulations of the interaction between mGluR1 and NMDA receptors reproduce the modulation of the NMDA-induced oscillations and the increase in the locomotor frequency. Secondly, mGluR1 activation depolarizes the membrane potential of neurons and consequently induces repetitive firing. These effects are due to an inhibition of a leak current responsible for setting the resting membrane potential. Interestingly, mGluR1 activates different signaling pathways to modulate NMDA current and leak conductance. Both effects require activation of Gproteins. The mGluR1-mediated inhibition of leak current requires PLC activation and release of Ca2+ from internal stores, as well as tyrosine kinase activation. The potentiation of NMDA current is not, however, dependent on an increase in intracellular Ca2+ or on tyrosine kinases. Thirdly, activation of mGluR1 receptors gives rise to a synthesis and release of endocannabinoids from postsynaptic neurons. The released endocannabinoids act as retrograde messengers which bind to presynaptic receptors and reduce glycinergic synaptic transmission. The reduced inhibitory transmission will result in an increase in the locomotor frequency. Hence, mGluR1 activation triggers the release of endocannabinoids which thus contribute to the mGlur1 mediated modulation of the locomotor network operation. Finally, endogenous activation of mGluR5 during locomotion decreases the burst frequency and produces long-lasting oscillations of the intracellular Ca2+ concentration. These oscillations are mediated through PLC and Ca2+ release from internal stores. Furthermore, they are also dependent on Ca2+ influx through L-type Ca2+ channels but do not involve PKC activation. Thus, mGluR5 seems to modulate the locomotor frequency via mechanisms involving oscillations of intracellular Ca 2+ concentration. In conclusion, the two group I mGluRs subtypes, mGluR1 and mGluR5, use separate signaling pathways and mediate opposite effects on locomotor activity. While the modulatory effects of mGluR5 seems to involve Ca2+ oscillations, those of rnGluR1 depend on different cellular and synaptic mechanisms which act in a synergistic manner to regulate the locomotor frequency.
|
|
| 8. |
- Kim, Min, et al.
(författare)
-
Primary fatty amides in plasma associated with brain amyloid burden, hippocampal volume, and memory in the European Medical Information Framework for Alzheimer's Disease biomarker discovery cohort
- 2019
-
Ingår i: Alzheimer's & Dementia. - : Elsevier. - 1552-5260 .- 1552-5279. ; 15:6, s. 817-827
-
Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: A critical and as-yet unmet need in Alzheimer's disease (AD) is the discovery of peripheral small molecule biomarkers. Given that brain pathology precedes clinical symptom onset, we set out to test whether metabolites in blood associated with pathology as indexed by cerebrospinal fluid (CSF) AD biomarkers.METHODS: This study analyzed 593 plasma samples selected from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery study, of individuals who were cognitively healthy (n = 242), had mild cognitive impairment (n = 236), or had AD-type dementia (n = 115). Logistic regressions were carried out between plasma metabolites (n = 883) and CSF markers, magnetic resonance imaging, cognition, and clinical diagnosis.RESULTS: Eight metabolites were associated with amyloid β and one with t-tau in CSF, these were primary fatty acid amides (PFAMs), lipokines, and amino acids. From these, PFAMs, glutamate, and aspartate also associated with hippocampal volume and memory.DISCUSSION: PFAMs have been found increased and associated with amyloid β burden in CSF and clinical measures.
|
|
| 9. |
- Landgren, Sara, 1980, et al.
(författare)
-
A novel ARC gene polymorphism is associated with reduced risk of Alzheimer's disease
- 2012
-
Ingår i: Journal of Neural Transmission. - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 119:7, s. 833-842
-
Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is the most common neurodegenerative disease, and is clinically characterized by cognitive disturbances and the accumulation of the amyloid beta (A beta) peptides in plaques in the brain. Recent studies have shown the links between AD and the immediate-early gene Arc (activity-regulated cytoskeleton-associated protein), involved in synaptic plasticity and memory consolidation. For example, AD mouse models show a decreased expression of Arc mRNA in the brain. In additional, acute A beta application to brain slices leads to a widespread ARC protein diffusion, unlike the normal defined localization to synapses. In this study, we investigated genetic variation in human ARC and the risk of developing AD. To this end, we genotyped 713 subjects diagnosed with AD and 841 controls without dementia. ARC was sequenced in a group of healthy individuals, and seven previously known SNPs and three novel SNPs were identified. Two of the newly found SNPs were intronic and one, +2852(G/A), was located in the 3'UTR. Three tag SNPs were selected, including the novel SNP +2852(G/A), to relate to risk of AD, Mini Mental State Examination (MMSE) scores and cerebrospinal fluid (CSF) biomarker levels of total tau (T-tau), hyperphosphorylated tau181 (P-tau(181)) and A beta(1-42). The AA genotype of the newly found 3'-UTR SNP +2852(A/G), was associated with a decreased risk of AD (p (c) = 0.005; OR = 0.74; 95 % CI: 0.61-0.89). No associations of single SNPs or haplotypes with MMSE score or CSF biomarkers were found. Here we report a novel ARC SNP associated with a reduced risk of developing AD. To our knowledge, this is the first study associating a gene variant of ARC with any disease. The location of the SNP within the 3'UTR indicates that dendritic targeting of ARC mRNA could be involved in the molecular mechanisms underlying this protective function. However, further investigation of the importance of this SNP for ARC function, ARC processing and the pathology of AD is needed.
|
|
| 10. |
|
|
