Authors

A. Marutle; M. Ohmitsu; M. Nilbratt; N. H. Greig; A. Nordberg;K. Sugaya

Comments

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Abbreviated Journal Title

Proc. Natl. Acad. Sci. U. S. A.

Keywords

amyloid precursor protein; transplantation; immunohistochernistry; neurogenesis; Alzheimer's disease; AMYLOID PRECURSOR PROTEIN; PROGENITOR CELLS; BETA-PEPTIDE; EXPRESSION; PATTERN; MESSENGER-RNA; RAT-BRAIN; IN-VITRO; DISEASE; NEUROGENESIS; PHOSPHORYLATION; Multidisciplinary Sciences

Abstract

In a previous study, we found that human neural stem cells (HNSCs) exposed to high concentrations of secreted amyloid-precursor protein (sAPP) in vitro differentiated into mainly astrocytes, suggesting that pathological alterations in APP processing during neurodegenerative conditions such as Alzheimer's disease (AD) may prevent neuronal differentiation of HNSCs. Thus, successful neuroplacement therapy for AD may require regulating APP expression to favorable levels to enhance neuronal differentiation of HNSCs. Phenserine, a recently developed cholinesterase inhibitor (ChEI), has been reported to reduce APP levels in vitro and in vivo. In this study, we found reductions of APP and glial fibrillary acidic protein (GFAP) levels in the hippocampus of APP23 mice after 14 days treatment with (+)-phenserine (25 mg/kg) lacking ChEI activity. No significant change in APP gene expression was detected, suggesting that (+)-phenserine decreases APP levels and reactive astrocytes by posttranscription regulation. HNSCs transplanted into (+)-phenserine-treated APP23 mice followed by an additional 7 days of treatment with (+)-phenserine migrated and differentiated into neurons in the hippocampus and cortex after 6 weeks. Moreover, (+)-phenserine significantly increased neuronal differentiation of implanted HNSCs in hippocampal and cortical regions of APP23 mice and in the CA1 region of control mice. These results indicate that (+)-phenserine reduces APP protein in vivo and increases neuronal differentiation of HNSCs. Combination use of HNSC transplantation and treatment with drugs such as (+)phenserine that modulate APP levels in the brain may be a useful tool for understanding mechanisms regulating stem cell migration and differentiation during neurodegenerative conditions in AD.

Journal Title

Proceedings of the National Academy of Sciences of the United States of America

Volume

104

Issue/Number

30

Publication Date

1-1-2007

Document Type

Article

Language

English

First Page

12506

Last Page

12511

WOS Identifier

WOS:000248472100050

ISSN

0027-8424

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