Dysregulation of the retromer complex system in Down syndrome.

OBJECTIVE: Most of Down syndrome (DS) patients develop Alzheimer's disease (AD) neuropathology by age 40. Although this increased susceptibility to AD in DS is thought to be primarily due to triplication of the amyloid precursor protein located on chromosome 21, the precise molecular mechanisms are not well understood. Recent evidence has implicated defective protein sorting and trafficking secondary to deficiencies in retromer complex proteins in AD pathogenesis. Thus, the objective of the present study is to assess the retromer complex system in DS. METHODS: Human post-mortem brain tissue and fibroblasts from subjects with DS and healthy controls were examined for the various retromer protein components using western blot analysis and RT-qPCR. RESULTS: Retromer recognition core proteins were significantly decreased in DS fibroblasts, and in both the hippocampi and cortices of young (age 15-40 years old) and aged (40-65 years old) DS subjects compared to controls. Correlation analyses showed a significant inverse relationship between recognition core proteins and levels of soluble forms of Abeta 1-40 and 1-42 in both hippocampus (n=33, Spearman=-0.59 to -0.38, p