Long-term enzyme replacement therapy improves neurocognitive functioning and hippocampal synaptic plasticity in immune-tolerant alpha-mannosidosis mice
Alpha-mannosidosis is a glycoproteinosis caused by deficiency of lysosomal acid alpha-mannosidase (LAMAN), which markedly affects neurons of the central nervous system (CNS), and causes pathognomonic intellectual dysfunction in the clinical condition. Cognitive improvement consequently remains a maj...
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doaj-69731922a1654397bfd10619a9c92c072021-03-22T12:45:42ZengElsevierNeurobiology of Disease1095-953X2017-10-01106255268Long-term enzyme replacement therapy improves neurocognitive functioning and hippocampal synaptic plasticity in immune-tolerant alpha-mannosidosis miceStijn Stroobants0Markus Damme1Ann Van der Jeugd2Ben Vermaercke3Claes Andersson4Jens Fogh5Paul Saftig6Judith Blanz7Rudi D'Hooge8Laboratory of Biological Psychology, KU Leuven, Tiensestraat 102, 3000 Leuven, Belgium; Corresponding author.Institute of Biochemistry, University of Kiel, Olshausenstrasse 40, 24098 Kiel, GermanyLaboratory of Biological Psychology, KU Leuven, Tiensestraat 102, 3000 Leuven, BelgiumLaboratory of Biological Psychology, KU Leuven, Tiensestraat 102, 3000 Leuven, BelgiumZymenex A/S, Roskildevej 12C, 3400 Hillerød, DenmarkZymenex A/S, Roskildevej 12C, 3400 Hillerød, DenmarkInstitute of Biochemistry, University of Kiel, Olshausenstrasse 40, 24098 Kiel, GermanyInstitute of Biochemistry, University of Kiel, Olshausenstrasse 40, 24098 Kiel, GermanyLaboratory of Biological Psychology, KU Leuven, Tiensestraat 102, 3000 Leuven, BelgiumAlpha-mannosidosis is a glycoproteinosis caused by deficiency of lysosomal acid alpha-mannosidase (LAMAN), which markedly affects neurons of the central nervous system (CNS), and causes pathognomonic intellectual dysfunction in the clinical condition. Cognitive improvement consequently remains a major therapeutic objective in research on this devastating genetic error. Immune-tolerant LAMAN knockout mice were developed to evaluate the effects of enzyme replacement therapy (ERT) by prolonged administration of recombinant human enzyme. Biochemical evidence suggested that hippocampus may be one of the brain structures that benefits most from long-term ERT. In the present functional study, ERT was initiated in 2-month-old immune-tolerant alpha-mannosidosis mice and continued for 9 months. During the course of treatment, mice were trained in the Morris water maze task to assess spatial-cognitive performance, which was related to synaptic plasticity recordings and hippocampal histopathology. Long-term ERT reduced primary substrate storage and neuroinflammation in hippocampus, and improved spatial learning after mid-term (10 weeks+) and long-term (30 weeks+) treatment. Long-term treatment substantially improved the spatial-cognitive abilities of alpha-mannosidosis mice, whereas the effects of mid-term treatment were more modest. Detailed analyses of spatial memory and spatial-cognitive performance indicated that even prolonged ERT did not restore higher cognitive abilities to the level of healthy mice. However, it did demonstrate marked therapeutic effects that coincided with increased synaptic connectivity, reflected by improvements in hippocampal CA3-CA1 long-term potentiation (LTP), expression of postsynaptic marker PSD-95 as well as postsynaptic density morphology. These experiments indicate that long-term ERT may hold promise, not only for the somatic defects of alpha-mannosidosis, but also to alleviate cognitive impairments of the disorder.http://www.sciencedirect.com/science/article/pii/S0969996117301663Enzyme replacement therapyLysosomal storage disorderAlpha-mannosidosisSynaptic plasticityLong-term potentiationHippocampus |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Stijn Stroobants Markus Damme Ann Van der Jeugd Ben Vermaercke Claes Andersson Jens Fogh Paul Saftig Judith Blanz Rudi D'Hooge |
spellingShingle |
Stijn Stroobants Markus Damme Ann Van der Jeugd Ben Vermaercke Claes Andersson Jens Fogh Paul Saftig Judith Blanz Rudi D'Hooge Long-term enzyme replacement therapy improves neurocognitive functioning and hippocampal synaptic plasticity in immune-tolerant alpha-mannosidosis mice Neurobiology of Disease Enzyme replacement therapy Lysosomal storage disorder Alpha-mannosidosis Synaptic plasticity Long-term potentiation Hippocampus |
author_facet |
Stijn Stroobants Markus Damme Ann Van der Jeugd Ben Vermaercke Claes Andersson Jens Fogh Paul Saftig Judith Blanz Rudi D'Hooge |
author_sort |
Stijn Stroobants |
title |
Long-term enzyme replacement therapy improves neurocognitive functioning and hippocampal synaptic plasticity in immune-tolerant alpha-mannosidosis mice |
title_short |
Long-term enzyme replacement therapy improves neurocognitive functioning and hippocampal synaptic plasticity in immune-tolerant alpha-mannosidosis mice |
title_full |
Long-term enzyme replacement therapy improves neurocognitive functioning and hippocampal synaptic plasticity in immune-tolerant alpha-mannosidosis mice |
title_fullStr |
Long-term enzyme replacement therapy improves neurocognitive functioning and hippocampal synaptic plasticity in immune-tolerant alpha-mannosidosis mice |
title_full_unstemmed |
Long-term enzyme replacement therapy improves neurocognitive functioning and hippocampal synaptic plasticity in immune-tolerant alpha-mannosidosis mice |
title_sort |
long-term enzyme replacement therapy improves neurocognitive functioning and hippocampal synaptic plasticity in immune-tolerant alpha-mannosidosis mice |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2017-10-01 |
description |
Alpha-mannosidosis is a glycoproteinosis caused by deficiency of lysosomal acid alpha-mannosidase (LAMAN), which markedly affects neurons of the central nervous system (CNS), and causes pathognomonic intellectual dysfunction in the clinical condition. Cognitive improvement consequently remains a major therapeutic objective in research on this devastating genetic error. Immune-tolerant LAMAN knockout mice were developed to evaluate the effects of enzyme replacement therapy (ERT) by prolonged administration of recombinant human enzyme. Biochemical evidence suggested that hippocampus may be one of the brain structures that benefits most from long-term ERT. In the present functional study, ERT was initiated in 2-month-old immune-tolerant alpha-mannosidosis mice and continued for 9 months. During the course of treatment, mice were trained in the Morris water maze task to assess spatial-cognitive performance, which was related to synaptic plasticity recordings and hippocampal histopathology. Long-term ERT reduced primary substrate storage and neuroinflammation in hippocampus, and improved spatial learning after mid-term (10 weeks+) and long-term (30 weeks+) treatment. Long-term treatment substantially improved the spatial-cognitive abilities of alpha-mannosidosis mice, whereas the effects of mid-term treatment were more modest. Detailed analyses of spatial memory and spatial-cognitive performance indicated that even prolonged ERT did not restore higher cognitive abilities to the level of healthy mice. However, it did demonstrate marked therapeutic effects that coincided with increased synaptic connectivity, reflected by improvements in hippocampal CA3-CA1 long-term potentiation (LTP), expression of postsynaptic marker PSD-95 as well as postsynaptic density morphology. These experiments indicate that long-term ERT may hold promise, not only for the somatic defects of alpha-mannosidosis, but also to alleviate cognitive impairments of the disorder. |
topic |
Enzyme replacement therapy Lysosomal storage disorder Alpha-mannosidosis Synaptic plasticity Long-term potentiation Hippocampus |
url |
http://www.sciencedirect.com/science/article/pii/S0969996117301663 |
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