doi: 10.1073/pnas.0802545105. Epub 2008 May 14.
Retromer deficiency observed in Alzheimer's disease causes hippocampal dysfunction, neurodegeneration, and Abeta accumulation
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- PMID:18480253
- PMCID: PMC2386077
- DOI: 10.1073/pnas.0802545105
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Retromer deficiency observed in Alzheimer's disease causes hippocampal dysfunction, neurodegeneration, and Abeta accumulation
Alim Muhammad et al. Proc Natl Acad Sci U S A..
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Abstract
Although deficiencies in the retromer sorting pathway have been linked to late-onset Alzheimer's disease, whether these deficiencies underlie the disease remains unknown. Here we characterized two genetically modified animal models to test separate but related questions about the effects that retromer deficiency has on the brain. First, testing for cognitive defects, we investigated retromer-deficient mice and found that they develop hippocampal-dependent memory and synaptic dysfunction, which was associated with elevations in endogenous Abeta peptide. Second, testing for neurodegeneration and amyloid deposits, we investigated retromer-deficient flies expressing human wild-type amyloid precursor protein (APP) and human beta-site APP-cleaving enzyme (BACE) and found that they develop neuronal loss and human Abeta aggregates. By recapitulating features of the disease, these animal models suggest that retromer deficiency observed in late-onset Alzheimer's disease can contribute to disease pathogenesis.
Conflict of interest statement
The authors declare no conflict of interest.
Figures
Retromer deficiency causes hippocampal-dependent memory and synaptic dysfunction. (a) (Top) The retromer sorting pathway, as first described in yeast, is made up of a multimeric retromer complex, including VPS35 and VPS26, and a retromer-binding receptor, VPS10. (Middle andBottom) SorLA and sortilin are VPS10-containing receptors that coimmunoprecipitate with VPS35 in the mouse brain. hom, homogenate; cont, no primary antibody control; co-IP, coimmunoprecipate. (b) Retromer-deficient mice, VPS26 heterozygote KO mice (+/−), have diminished brain levels of VPS26 and VPS35, as shown in bar graphs representing mean levels (normalized to actin) measured from the brains of five +/− and five wild-type (+/+) mice. Immunoblots (Lower Left) and immunocytochemistry (Lower Right) are shown for individual examples. (c) Retromer-deficient mice have defects in hippocampal-dependent memory, as measured in the radial-arm water maze (Upper). The mean number of errors (y axis) are shown for retromer-deficient mice (solid line, +/−) and for wild-type littermates (stippled line, +/+) measured every 90 s during the first four trials and then after a 30-min delay. Retromer-deficient mice have defects in long-term potentiation (Lower), recorded from acute hippocampal slices (filled circles, +/−; open circles, +/+).
Retromer deficiency elevates levels of endogenous Aβ in the mouse brain. (a) Retromer-deficient mice (+/−) have elevated levels of endogenous Aβ40 and Aβ42 (Upper, measured in 16 +/− and 18 +/+ mice). Retromer-deficient mice (+/−) have elevated levels of endogenous sAPPβ (Lower Left). Levels of sAPPβ and Aβ are significantly correlated (Lower Right). (b) Immunoblots from the brains of three retromer-deficient mice (+/−) and two wild-type littermates (+/+) show that, except for sAPPβ, no differences were observed for full-length APP, CTFs, or sAPPα. (c) Administration of the γ-secretase inhibitor L-685,458 rescues the LTP defects in retromer-deficient mice (filled circles, +/−; open circles, +/+).
Retromer deficiency elevates levels of human Aβ in the brains of flies expressing human APP and BACE and causes neurodegeneration. (a) Retromer-deficient flies (+/− for VPS35) expressing human APP and human BACE have elevated brain levels of human Aβ compared with control flies (+/+ for VPS35) expressing human APP and human BACE. Immunoblots inUpper show individual examples (note reduction in full-length APP), and the bar graph inLower shows means levels from 10 flies per genotype. (b) High-magnification view of frontal brain sections at approximately midbrain from control (+/+) and retromer-deficient (+/−) flies expressing human APP and human BACE stained with 4G8 antibody to detect Aβ deposits (arrowheads). These deposits are larger and more numerous in the retromer-deficient flies. Each section shows a portion of the central neuropil located to the left and adjacent to the esophagus (Es). Anterior is toward the top. (c) Frontal brain sections at the midbrain level shown for control (+/+) and retromer-deficient (+/−) flies expressing human wild-type APP and human BACE. The left half of the central brain and optic lobe are shown. Esophagus is in the middle of the section at the right margin. Extensive neurodegeneration can be seen in the neuropil of retromer-deficient flies. (Scale bar: 50 μm.)
References
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