Role of RanBP9 on amyloidogenic processing of APP and synaptic protein levels in the mouse brain

    Authors

    M. K. Lakshmana; C. D. Hayes; S. P. Bennett; E. Bianchi; K. M. Reddy; E. H. Koo;D. E. Kang

    Comments

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    Abbreviated Journal Title

    Faseb J.

    Keywords

    Alzheimer's disease; transgenic mice; null mice; synapses; PRECURSOR-PROTEIN; ALZHEIMERS-DISEASE; BETA-SECRETASE; COGNITIVE; IMPAIRMENT; ENDOCYTIC PATHWAY; BINDING PROTEIN; DENSITY; DOMAIN; ALPHA; BACE1; Biochemistry & Molecular Biology; Biology; Cell Biology

    Abstract

    We previously reported that RanBP9 binds low-density lipoprotein receptor-related protein (LRP), amyloid precursor protein (APP), and BACE1 and robustly increased A beta generation in a variety of cell lines and primary neuronal cultures. To confirm the physiological/pathological significance of this phenotype in vivo, we successfully generated transgenic mice overexpressing RanBP9 as well as RanBP9-null mice. Here we show that RanBP9 overexpression resulted in > 2-fold increase in A beta 40 levels as early as 4 mo of age. A sustained increase in A beta 40 levels was seen at 12 mo of age in both CHAPS-soluble and formic acid (FA)-soluble brain fractions. In addition, A beta 42 levels were also significantly increased in FA-soluble fractions at 12 mo of age. More important, increased A beta levels were translated to increased deposition of amyloid plaques. In addition, RanBP9 overexpression significantly decreased the levels of synaptophysin and PSD-95 proteins. Conversely, RanBP9-null mice showed increased levels of synaptophysin, PSD-95, and drebrin A protein levels. Given that loss of synapses is the best pathological correlate of cognitive deficits in Alzheimer's disease (AD), increased A beta levels by RanBP9 observed in the present study provides compelling evidence that RanBP9 may indeed play a key role in the etiology of AD. If so, RanBP9 provides a great opportunity to develop novel therapy for AD.-Lakshmana, M. K., Hayes, C. D., Bennett, S. P., Bianchi, E., Reddy, K. M., Koo, E. H., Kang, D. E. Role of RanBP9 on amyloidogenic processing of APP and synaptic protein levels in the mouse brain. FASEB J. 26, 2072-2083 (2012). www.fasebj.org

    Journal Title

    Faseb Journal

    Volume

    26

    Issue/Number

    5

    Publication Date

    1-1-2012

    Document Type

    Article

    Language

    English

    First Page

    2072

    Last Page

    2083

    WOS Identifier

    WOS:000303680800033

    ISSN

    0892-6638

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