P1‐090: The effects of Alzheimer's disease associated transferrin variants on APP metabolism
Year: 2010
Type: article
Abstract: Alzheimer's disease (AD) is a neurodegenerative disease characterized by neuronal loss and the accumulation of β-amyloid plaques and neurofibrillary tangles in the brain. The amyloid hypothesis proposes that changes in amyloid precursor protein (APP) and/or Aß homeostasis leads to the aggregation of Aß and deposition in plaques and that these events are sufficient to initiate the cascade of pathologic abnormalities associated with AD. We have utilized cerebrospinal fluid (CSF) Aß levels as a quantitative endophenotype to identify genes that influence Aß levels and contribute to disease pathogenesis. Our group has previously demonstrated that variation in APOE, angiotensin converting enzyme (ACE), death associated protein kinase 1(DAPK1) and transferrin (TF) are associated with risk for AD via an Aβ related mechanism. Moreover, a single nucleotide polymorphism (SNP) in transferrin (rs1049296, P589S) was shown to be associated with an increased Aβ42/40 ratio. In this study, we sought to detect additional AD-associated variants in the TF gene by sequencing the exons and promoter regions of TF in individuals from our CSF study with most extreme Aβ40, Aβ42, or Aβ40/42 ratio (top or bottom 5%). We identified four non-synonymous SNPs in TF in individuals in the top 5% of CSF-Aβ40/42 ratios: two novel variants (R343W and G671E) and two known variants (G277S and P589S). To determine how these TF variants affect APP processing, we used site-directed mutagenesis and a cell culture assay. We demonstrate that co-expression of APP and wild-type transferrin results in reduced levels of full-length APP but does not change levels of gamma-secretase cleavage fragments of APP. Furthermore, when wild-type or mutant transferrin was co-expressed with APP, we found that APP is less stable in the presence of wild-type transferrin and that APP is more stable in the presence of mutant transferrin. Together, this evidence suggests that transferrin may influence AD pathogenesis by modulating the homeostasis of full-length APP.
Source: Alzheimer s & Dementia
Institutions: Washington University in St. Louis, Brigham Young University
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W1996035780