Premium
P2–014: Dysregulation of brain APP in the Ts65Dn Down syndrome mouse
Author(s) -
Choi Jennifer H.K.,
Diaz Nichole S.,
Mazzella Matthew J.,
Peterson Jesse N.,
Cataldo Anne M.,
Ginsberg Stephen D.,
Levy Efrat,
Nixon Ralph A.,
Mathews Paul M.
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.851
Subject(s) - chromosome 21 , amyloid precursor protein , basal forebrain , down syndrome , hippocampus , cholinergic , hippocampal formation , biology , neocortex , striatum , temporal cortex , cerebral cortex , endocrinology , medicine , microbiology and biotechnology , alzheimer's disease , gene , neuroscience , chromosome , genetics , disease , dopamine
Background: Ts65Dn mice are trisomic for a segment of murine chromosome 16 orthologous to the Down syndrome (DS) critical region of human chromosome 21, which includes the amyloid precursor protein (App) gene. The Ts65Dn mouse is a widely used model of human DS showing agedependent basal forebrain cholinergic degeneration and abnormalities in endocytosis seen selectively in Alzheimer’s disease (AD) and DS (Boiteau, et al., this meeting). Objective: We have examined APP expression and processing in the brains of Ts65Dn mice. Methods/Results: In spite of the additional App gene copy in Ts65Dn mice, we found APP holoprotein levels in the brains of 4-month-old trisomic mice to be similar to the levels seen in 2N littermates. Homogenates prepared from total brain, cingulate cortex, temporal cortex, hippocampus, and striatum of 12-month-old Ts65Dn mice, however, showed an 2-fold increase in APP levels. This increase is greater than predicted (1.5-fold) based upon the additional App gene copy, and is greater than the 1.4-fold increase in APP mRNA seen in individual CA1 pyramidal neurons obtained from 12-month-old Ts65Dn mice. Using a novel monoclonal antibody that recognizes murine sAPP (Mazzella, et al., this meeting), we determined that the levels of the proteolytic metabolites sAPP and sAPP were both 1.3-fold greater in the 12-month-old Ts65Dn mice than in 2N mice. A similar increase was seen in brain A 40 and A 42 levels. Unlike APP, sAPP, and A , the total levels of and -cleaved carboxy-terminal fragments of APP were found to be similar in Ts65Dn and 2N mice. Conclusions: While increased expression of APP is consistent with the additional App gene copy in Ts65Dn mice, the age-dependence of the APP holoprotein increase and the differential increases in APP holoprotein and its metabolites suggest that APP metabolism is altered in older Ts65Dn mice. Understanding APP metabolism in this model is likely to give insight into the mechanism by which AD neuropathology develops in DS individuals and may suggest an interrelationship between APP metabolism and neurodegeneration in Ts65Dn mice.