Low prevalence of APP duplications in Swedish and Finnish patients with early-onset Alzheimer's disease

Blom, Elin; Viswanathan, Jayashree; Kilander, Lena; Helisalmi, Seppo; Lannfelt, Lars; Ingelsson, Martin; Glaser, Anna; Hiltunen, Mikko

doi:10.1038/sj.ejhg.5201966

Cited by 29 publications

(23 citation statements)

References 19 publications

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“…The frequency of APP duplication was reported to be 8% in the French dominant EO-FAD cohort1 and less than 2% in the Dutch EO-FAD cohort 3. Subsequent screening analysis of large Swedish and Finnish EO-AD cohorts, however, failed to detect APP duplication 13. We report here the case of two unrelated Japanese EO-FAD families with APP duplication.…”

Section: Discussionmentioning

confidence: 81%

Identification of independent APP locus duplication in Japanese patients with early-onset Alzheimer disease

Kasuga

Shimohata

Nishimura

et al. 2009

Journal of Neurology, Neurosurgery & Psychiatry

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Section: Discussionmentioning

confidence: 81%

Identification of independent APP locus duplication in Japanese patients with early-onset Alzheimer disease

Kasuga

Shimohata

Nishimura

et al. 2009

Journal of Neurology, Neurosurgery & Psychiatry

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“…12,24 However, in a previous clinical series of Swedish and Finnish familial eoAD patients, no APP duplications were identified. 33 The patients in the present series were not systematically screened for APP duplications. Only a few PSEN1 mutations have been identified in Finland so far.…”

Section: Discussionmentioning

confidence: 99%

Molecular Genetic Analysis of the APP, PSEN1, and PSEN2 Genes in Finnish Patients With Early-onset Alzheimer Disease and Frontotemporal Lobar Degeneration

Krüger

Moilanen²,

Majamaa³

et al. 2012

Alzheimer Disease &Amp; Associated Disorders

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Mutations in 3 genes, amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2), have been identified as causing a proportion of early-onset Alzheimer disease (eoAD) cases. A few PSEN mutations have also been previously detected in patients with frontotemporal lobar degeneration (FTLD). In order to evaluate the role of these genes in a clinical series of Finnish eoAD and FTLD patients, we sequenced exons 16 and 17 of the APP gene and the coding regions of the PSEN1 and PSEN2 genes in 140 eoAD and 66 FTLD patients. No pathogenic mutations were identified in the cohort. The E318G variant was detected with similar frequencies in the cases with eoAD and FTLD and the healthy controls, therefore, showing no association between E318G and eoAD. Furthermore, the PSEN2 R71W variant seems to be nonpathogenic, because it was present in our healthy controls. Mutations in the PSEN1, PSEN2, and APP genes seem to be rare in this population, as these genes exhibited no pathogenic mutations in our cohort of eoAD and FTLD patients even though about 40% of the cases were familial ones. This suggests the involvement of other, still unknown genetic factors in the pathogenesis of these diseases.

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“…Similarly, only 40% reduction of BACE1 protein by directly injected siRNA-expressing lentivirus significantly reduced AD pathology (Singer et al, 2005). Additionally, duplication of the APP gene with a 1.5-fold gene dosage increase is known to cause familial AD (Blom et al, 2008), suggesting that a 33% reduction of APP expression is enough to prevent the disease. Therefore, a more than 60% reduction of BACE1 with our vector system can be expected to reduce Ab load and improve AD phenotype.…”

Section: Discussionmentioning

confidence: 99%

High-Density Lipoprotein FacilitatesIn VivoDelivery of α-Tocopherol–Conjugated Short-Interfering RNA to the Brain

et al. 2011

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We originally reported the use of vitamin E (a-tocopherol) as an in vivo vector of short-interfering RNA (siRNA) to the liver. Here, we apply our strategy to the brain. By combining high-density lipoprotein (HDL) as a second carrier with a-tocopherol-conjugated siRNA (Toc-siRNA) in the brain, we achieved dramatic improvement of siRNA delivery to neurons. After direct intracerebroventricular (ICV) infusion of Toc-siRNA/HDL for 7 days, extensive and specific knock-down of a target gene, b-site amyloid precursor protein cleaving enzyme 1 (BACE1), was observed in both mRNA and protein levels, especially in the cerebral cortex and hippocampus. This new delivery method achieved a much more prominent down-regulation effect than conventional silencing methods of the brain gene, i.e., ICV infusion of nonconjugated siRNA or oligonucleotides. With only 3 nmol Toc-siRNA with HDL, BACE1 mRNA in the parietal cortex could be reduced by *70%. We suppose that this dramatic improvement of siRNA delivery to the brain is due to the use of lipoprotein receptor-mediated endocytosis because the silencing efficiency was significantly increased by binding of Toc-siRNA to the lipoprotein, and in contrast, was clearly decreased in lipoprotein-receptor knockout mice. These results suggest exogenous siRNA could be used clinically for otherwise incurable neurological diseases.

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Low prevalence of APP duplications in Swedish and Finnish patients with early-onset Alzheimer's disease

Cited by 29 publications

References 19 publications

Identification of independent APP locus duplication in Japanese patients with early-onset Alzheimer disease

Identification of independent APP locus duplication in Japanese patients with early-onset Alzheimer disease

Molecular Genetic Analysis of the APP, PSEN1, and PSEN2 Genes in Finnish Patients With Early-onset Alzheimer Disease and Frontotemporal Lobar Degeneration

High-Density Lipoprotein FacilitatesIn VivoDelivery of α-Tocopherol–Conjugated Short-Interfering RNA to the Brain

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