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

ABSTRACT: We previously reported that RanBP9 binds low-density lipoprotein receptor-related protein (LRP), amyloid precursor protein (APP), and BACE1 and robustly increased A? 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?40 levels as early as 4 mo of age. A sustained increase in A?40 levels was seen at 12 mo of age in both CHAPS-soluble and formic acid (FA)-soluble brain fractions. In addition, A?42 levels were also significantly increased in FA-soluble fractions at 12 mo of age. More important, increased A? 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? 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.

SUBMITTER: Lakshmana MK 

PROVIDER: S-EPMC3336780 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature