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  • 1. Blom, Elin S
    et al.
    Wang, Yijing
    Skoglund, Lena
    Uppsala universitet.
    Hansson, Anita C
    Ubaldi, Massimo
    Lourdusamy, Anbarasu
    Sommer, Wolfgang H
    Mielke, Matthew
    Hyman, Bradley T
    Heilig, Markus
    Lannfelt, Lars
    Nilsson, Lars N G
    Ingelsson, Martin
    Increased mRNA Levels of TCF7L2 and MYC of the Wnt Pathway in Tg-ArcSwe Mice and Alzheimer's Disease Brain.2010In: International Journal of Alzheimer's Disease, ISSN 2090-8024, E-ISSN 2090-0252, Vol. 2011Article in journal (Refereed)
    Abstract [en]

    Several components in the Wnt pathway, including β-catenin and glycogen synthase kinase 3 beta, have been implied in AD pathogenesis. Here, mRNA brain levels from five-month-old tg-ArcSwe and nontransgenic mice were compared using Affymetrix microarray analysis. With surprisingly small overall changes, Wnt signaling was the most affected pathway with altered expression of nine genes in tg-ArcSwe mice. When analyzing mRNA levels of these genes in human brain, transcription factor 7-like 2 (TCF7L2) and v-myc myelocytomatosis viral oncogene homolog (MYC), were increased in Alzheimer's disease (AD) (P < .05). Furthermore, no clear differences in TCF7L2 and MYC mRNA were found in brains with frontotemporal lobar degeneration, suggesting that altered regulation of these Wnt-related genes could be specific to AD. Finally, mRNA levels of three neurogenesis markers were analyzed. Increased mRNA levels of dihydropyrimidinase-like 3 were observed in AD brain, suggesting that altered Wnt pathway regulation may signify synaptic rearrangement or neurogenesis.

  • 2. Giedraitis, V
    et al.
    Hedlund, M
    Skoglund, Lena
    Uppsala universitet.
    Blom, E
    Ingvast, S
    Brundin, R
    Lannfelt, L
    Glaser, A
    New Alzheimer's disease locus on chromosome 8.2006In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 43, no 12Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Family history is one of the most consistent risk factors for dementia. Therefore, analysis of families with a distinct inheritance pattern of disease can be a powerful approach for the identification of previously unknown disease genes.

    OBJECTIVE: To map susceptibility regions for Alzheimer's disease.

    METHODS: A complete genome scan with 369 microsatellite markers was carried out in 12 extended families collected in Sweden. Age at disease onset ranged from 53 to 78 years, but in 10 of the families there was at least one member with age at onset of < or =65 years. Mutations in known early-onset Alzheimer's disease susceptibility genes have been excluded. All people were genotyped for APOE, but no clear linkage with the epsilon4 allele was observed.

    RESULTS: Although no common disease locus could be found in all families, in two families an extended haplotype was identified on chromosome 8q shared by all affected members. In one of the families, a non-parametric multimarker logarithm of the odds (LOD) score of 4.2 (p = 0.004) was obtained and analysis based on a dominant model showed a parametric LOD score of 2.4 for this region. All six affected members of this family shared a haplotype of 10 markers spanning about 40 cM. Three affected members in another family also shared a haplotype in the same region.

    CONCLUSION: On the basis of our data, we propose the existence of a dominantly acting Alzheimer's disease susceptibility locus on chromosome 8.

  • 3. Ingelsson, Martin
    et al.
    Ramasamy, Karunya
    Cantuti-Castelvetri, Ippolita
    Skoglund, Lena
    Uppsala universitet.
    Matsui, Toshifumi
    Orne, Jennifer
    Kowa, Hasimoto
    Raju, Susan
    Vanderburg, Charles R
    Augustinack, Jean C
    de Silva, Rohan
    Lees, Andrew J
    Lannfelt, Lars
    Growdon, John H
    Frosch, Matthew P
    Standaert, David G
    Irizarry, Michael C
    Hyman, Bradley T
    No alteration in tau exon 10 alternative splicing in tangle-bearing neurons of the Alzheimer's disease brain.2006In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 112, no 4Article in journal (Refereed)
    Abstract [en]

    Defective splicing of tau mRNA, promoting a shift between tau isoforms with (4R tau) and without (3R tau) exon 10, is believed to be a pathological consequence of certain tau mutations causing frontotemporal dementia. By assessing protein and mRNA levels of 4R tau and 3R tau in 27 AD and 20 control temporal cortex, we investigated whether altered tau splicing is a feature also in Alzheimer's disease (AD). However, apart from an expected increase of sarcosyl-insoluble tau in AD, there were no significant differences between the groups. Next, by laser-capture microscopy and quantitative PCR, we separately analyzed CA1 hippocampal neurons with and without neurofibrillary pathology from six of the AD and seven of the control brains. No statistically significant differences in 4R tau/3R tau mRNA were found between the different subgroups. Moreover, we confirmed the absence of significant ratio differences in a second data set with laser-captured entorhinal cortex neurons from four AD and four control brains. Finally, the 4R tau/3R tau ratio in CA1 neurons was roughly half of the ratio in temporal cortex, indicating region-specific differences in tau mRNA splicing. In conclusion, this study indicated region-specific and possibly cell-type-specific tau splicing but did not lend any support to overt changes in alternative splicing of tau exon 10 being an underlying factor in AD pathogenesis.

  • 4.
    Skoglund, Lena
    Uppsala universitet, Institutionen för folkhälso- och vårdvetenskap.
    Molecular Mechanisms of Frontotemporal Lobar Degeneration2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The aim of this thesis was to identify genetic factors involved in frontotemporal lobar degeneration (FTLD), a neurodegenerative disorder clinically characterised by a progressive change in personality, behaviour and language. FTLD is a genetically complex disorder and a positive family history is found in up to 40% of the cases.

    In 10-20% of the familial cases the disease can be explained by mutations in the gene encoding the microtubule associated protein tau (MAPT). In the first study we describe the clinical and neuropathological features of a Finnish family with FTLD caused by a mutation in MAPT. We also provide evidence that the pathogenic mechanism of this mutation is through altered splicing of MAPT transcripts.

    Recently, mutations in the gene encoding progranulin (PGRN) were identified as a major cause of FTLD. In the second study we describe a Swedish family with FTLD caused by a frameshift mutation in PGRN. We provide a clinical and neuropathological description of the family, as well as evidence that the pathogenicity of this mutation is through nonsense-mediated decay of the mutant mRNA transcripts and PGRN haploinsufficiency.

    In the third study we describe a novel PGRN splice site mutation and a previously described PGRN frameshift mutation, found in a mutation screen of 51 FTLD patients. We describe the clinical and neuropathological characteristics of the mutation carriers and demonstrate that haploinsufficiency is the pathogenic mechanism of the two mutations.

    In the fourth study we investigate the prevalence of PGRN and MAPT gene dosage alterations in 39 patients with FTLD. No gene dosage alterations were identified, indicating that variations in copy number of the PGRN and MAPT genes are not a common cause of disease, at least not in this FTLD patient collection.

  • 5.
    Skoglund, Lena
    et al.
    Department of Public Health and Caring Sciences, Uppsala University, Dag Hammarskjölds väg 20, 751 85, Uppsala, Sweden.
    Brundin, RoseMarie
    Department of Public Health and Caring Sciences, Uppsala University, Dag Hammarskjölds väg 20, 751 85, Uppsala, Sweden.
    Olofsson, Tommie
    Uppsala Univ, Dept Surg Sci, S-75185 Uppsala, Sweden.
    Kalimo, Hannu
    Univ Helsinki, Dept Pathol, Helsinki, Finland ; Uppsala Univ, Dept Genet & Pathol, S-75185 Uppsala, Sweden.
    Ingvast, Sofie
    Uppsala Univ, Dept Publ Hlth & Caring Sci, S-75185 Uppsala, Sweden.
    Blom, Elin
    Uppsala Univ, Dept Publ Hlth & Caring Sci, S-75185 Uppsala, Sweden.
    Giedraitis, Vilmantas
    Uppsala Univ, Dept Publ Hlth & Caring Sci, S-75185 Uppsala, Sweden.
    Ingelsson, Martin
    Uppsala Univ, Dept Publ Hlth & Caring Sci, S-75185 Uppsala, Sweden.
    Lannfelt, Lars
    Uppsala Univ, Dept Publ Hlth & Caring Sci, S-75185 Uppsala, Sweden.
    Basun, Hans
    Uppsala Univ, Dept Publ Hlth & Caring Sci, S-75185 Uppsala, Sweden.
    Glaser, Anna
    Uppsala Univ, Dept Publ Hlth & Caring Sci, S-75185 Uppsala, Sweden.
    Frontotemporal dementia in a large Swedish family is caused by a progranulin null mutation2009In: Neurogenetics, ISSN 1364-6745, E-ISSN 1364-6753, Vol. 10, no 1, p. 27-34Article in journal (Refereed)
  • 6.
    Skoglund, Lena
    et al.
    Uppsala Univ, Dept Publ Hlth & Caring Sci, SE-75185 Uppsala, Sweden.
    Ingvast, Sofie
    Uppsala Univ, Dept Publ Hlth & Caring Sci, SE-75185 Uppsala, Sweden.
    Matsui, Toshifumi
    Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA USA.
    Freeman, Stefanie H.
    Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA USA.
    Frosch, Matthew P.
    Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA USA.
    Brundin, Rosemarie
    Uppsala Univ, Dept Publ Hlth & Caring Sci, SE-75185 Uppsala, Sweden.
    Giedraitis, Vilmantas
    Uppsala Univ, Dept Publ Hlth & Caring Sci, SE-75185 Uppsala, Sweden.
    Growdon, John H.
    Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA USA.
    Hyman, Bradley T.
    Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA USA.
    Lannfelt, Lars
    Uppsala Univ, Dept Publ Hlth & Caring Sci, SE-75185 Uppsala, Sweden.
    Ingelsson, Martin
    Uppsala Univ, Dept Publ Hlth & Caring Sci, SE-75185 Uppsala, Sweden.
    Glaser, Anna
    Uppsala Univ, Dept Publ Hlth & Caring Sci, SE-75185 Uppsala, Sweden.
    No Evidence of PGRN or MAPT Gene Dosage Alterations in a Collection of Patients with Frontotemporal Lobar Degeneration2009In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 28, no 5, p. 471-475Article in journal (Refereed)
    Abstract [en]

    Background/Aims: Alterations in gene dosage have recently been associated with neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease, and deletions of the progranulin (PGRN) locus were recently described in patients with frontotemporal lobar degeneration (FTLD). FTLD is a genetically complex neurodegenerative disorder with mutations in the PGRN and the microtubule-associated protein tau (MAPT) genes being the most common known causes of familial FTLD. In this study, we investigated 39 patients with FTLD, previously found negative for mutations in PGRN and MAPT, for copy number alterations of these 2 genes. Methods: Gene dosage analysis of PGRN and MAPT was performed using multiplex ligation-dependent probe amplification. Results: We did not identify any PGRN or MAPT gene dosage variations in the 39 FTLD patients investigated. Conclusion: We therefore conclude that alterations in gene copy number of PGRN and MAPT are not a cause of disease in this collection of FTLD patients. Copyright (C) 2009 S. Karger AG, Basel

  • 7.
    Skoglund, Lena
    et al.
    Molecular Geriatrics, Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
    Matsui, Toshifumi
    Freeman, Stefanie
    Wallin, Anders
    Blom, Elin
    Frosch, Matthew P.
    Growdon, John H.
    Hyman, Bradley T.
    Lannfelt, Lars
    Ingelsson, Martin MD, PhD
    Glaser, Anna PhD
    Novel progranulin mutation detected in 2 patiens with FTLD2011In: Alzheimer Disease and Associated Disorders, ISSN 0893-0341, Vol. 25, no 2, p. 173-178Article in journal (Refereed)
  • 8.
    Skoglund, Lena
    et al.
    Uppsala universitet.
    Viitanen, M
    Kalimo, H
    Lannfelt, L
    Jönhagen, M E
    Ingelsson, M
    Glaser, A
    Herva, R
    The tau S305S mutation causes frontotemporal dementia with parkinsonism.2008In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 15, no 2Article in journal (Refereed)
    Abstract [en]

    Members of families with mutations in the tau gene are known to be heterogeneous in their clinical presentation, ranging from frontotemporal dementia to a clinical picture more resembling corticobasal degeneration or progressive supranuclear palsy. In this report, we describe a new phenotype for the tau S305S mutation, previously described as progressive supranuclear palsy. Clinically, the three affected family members showed alterations in personality and behaviour as well as cognitive decline and late levodopa-resistant parkinsonian symptoms, consistent with the diagnosis of frontotemporal dementia with parkinsonism linked to chromosome 17. One autopsied case displayed degeneration of the frontal and temporal lobes together with extensive tau pathology in both neurones and glial cells. Sarkosyl-soluble and -insoluble tau extracted from frontal cortex revealed a ratio shift with decreased levels of tau with three microtubule-binding repeats and increased levels of tau with four microtubule-binding repeats (4R tau). These findings provide further evidence for the clinical and pathological variation both within and between families with mutations in the tau gene. In addition, they support previous studies which demonstrate that the S305S mutation influences the splicing of tau exon 10 and results in an overproduction of 4R tau.

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