May 16, 2008

Retromer deficiency observed in Alzheimer's disease causes hippocampal dysfunction, neurodegeneration, and Abeta accumulation

Proceedings of the National Academy of Sciences of the United States of America
Alim MuhammadScott A Small

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.

  • References32
  • Citations94
  • References32
  • Citations94

Mentioned in this Paper

Familial Alzheimer Disease (FAD)
Pathogenic Aspects
Biochemical Pathway
Pathogenesis
Amyloid Beta Precursor Protein Measurement
Brain
Degenerative Diseases, Spinal Cord
Nerve Degeneration
APP wt Allele
Retrograde Degeneration

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