Browsing by Subject "Alzheimer disease"

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  • Oikari, Lotta E.; Pandit, Rucha; Stewart, Romal; Cuní-López, Carla; Quek, Hazel; Sutharsan, Ratneswary; Rantanen, Laura M.; Oksanen, Minna; Lehtonen, Sarka; de Boer, Carmela Maria; Polo, Jose M.; Götz, Jürgen; Koistinaho, Jari; White, Anthony R. (2020)
    The blood-brain barrier (BBB) presents a barrier for circulating factors, but simultaneously challenges drug delivery. How the BBB is altered in Alzheimer disease (AD) is not fully understood. To facilitate this analysis, we derived brain endothelial cells (iBECs) from human induced pluripotent stem cells (hiPSCs) of several patients carrying the familial AD PSEN1 mutation. We demonstrate that, compared with isogenic PSEN1 corrected and control iBECs, AD-iBECs exhibit altered tight and adherens junction protein expression as well as efflux properties. Furthermore, by applying focused ultrasound (FUS) that transiently opens the BBB and achieves multiple therapeutic effects in AD mouse models, we found an altered permeability to 3-5 kDa dextran as a model cargo and the amyloid-beta (A beta) peptide in AD-iBECs compared with control iBECs. This presents human-derived in vitro models of the BBB as a valuable tool to understand its role and properties in a disease context, with possible implications for drug delivery.
  • Konttinen, Henna; Cabral-da-Silva, Mauricio e Castro; Ohtonen, Sohvi; Wojciechowski, Sara; Shakirzyanova, Anastasia; Caligola, Simone; Giugno, Rosalba; Ishchenko, Yevheniia; Hernández, Damián; Fazaludeen, Mohammad Feroze; Eamen, Shaila; Budia, Mireia Gómez; Fagerlund, Ilkka; Scoyni, Flavia; Korhonen, Paula; Huber, Nadine; Haapasalo, Annakaisa; Hewitt, Alex W.; Vickers, James; Smith, Grady C.; Oksanen, Minna; Graff, Caroline; Kanninen, Katja M.; Lehtonen, Sarka; Propson, Nicholas; Schwartz, Michael P.; Pébay, Alice; Koistinaho, Jari; Ooi, Lezanne; Malm, Tarja (2019)
    Summary Here we elucidate the effect of Alzheimer disease (AD)-predisposing genetic backgrounds, APOE4, PSEN1ΔE9, and APPswe, on functionality of human microglia-like cells (iMGLs). We present a physiologically relevant high-yield protocol for producing iMGLs from induced pluripotent stem cells. Differentiation is directed with small molecules through primitive erythromyeloid progenitors to re-create microglial ontogeny from yolk sac. The iMGLs express microglial signature genes and respond to ADP with intracellular Ca2+ release distinguishing them from macrophages. Using 16 iPSC lines from healthy donors, AD patients and isogenic controls, we reveal that the APOE4 genotype has a profound impact on several aspects of microglial functionality, whereas PSEN1ΔE9 and APPswe mutations trigger minor alterations. The APOE4 genotype impairs phagocytosis, migration, and metabolic activity of iMGLs but exacerbates their cytokine secretion. This indicates that APOE4 iMGLs are fundamentally unable to mount normal microglial functionality in AD.
  • Perttilä, Niko; Ohman, H.; Strandberg, T. E.; Kautiainen, H.; Raivio, M.; Laakkonen, M. -L.; Savikko, N.; Tilvis, R. S.; Pitkala, K. H. (2016)
    Introduction: To investigate how frailty status affects the outcome of exercise intervention among home-dwelling participants with Alzheimer disease (AD). Methods: This is a sub-group analysis of a randomized controlled trial. In this trial, home-dwelling participants with AD received either home-based or group-based exercise twice a week for one year (n = 129); the control group received normal care (n = 65). Both the intervention and control group were subdivided into two groups according to modified Fried criteria: prefrail (0-1 criteria) and advanced frailty (2-5 criteria). The Functional Independence Measure (FIM) and number of falls per person-years served as outcome measures. Results: Whereas there was no significant difference in FIM between the prefrail intervention (PRI) and control (PRC) groups at 3 or 6 months, the PRI group deteriorated significantly slower at 12 months (-6.6 [95% CI -8.6 to -4.5] for PRI and -11.1 [95% CI -13.9 to -8.3] for PRC; P = 0.010). Similarly, there was no significant difference between the advanced frailty intervention (AFI) and control (AFC) groups at 3 months, but the difference became significant at 6 months (-8.1 [95% CI -11.1 to -5.2] for AFI and -15.5 [95% CI -20.0 to -11.1] for AFC; P = 0.007) and at 12 months (-8.9 [95% CI -11.9 to -5.9] for AFI and -15.3 [95% CI -20.2 to -10.3] for AFC; P = 0.031). There was also a significant difference in the number of falls in favor of PRI and AFI groups compared to their respective control groups. Conclusion: A long-term exercise intervention benefited people with AD regardless of their stage of frailty. Trial registration: : ACTRN12608000037303. (C) 2016 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.