Opposing roles of the LDL receptor-related protein (LRP1) and the LDL receptor-related protein 1B (LRP1B) in beta-amyloid precursor protein (APP) trafficking and processing

Alzheimer's disease (AD) is the most common form of dementia in the elderly. Although the cause of AD dementia is still unclear, it is likely related to deposits of characteristic neurofibrillary tangles and amyloid plaques found in AD brains. Amyloid plaques are composed of amyloid-beta peptides (Abeta) derived from proteolytic processing of beta-amyloid precursor protein (APP). Inherited mutations within the APP gene lead to early onset AD; however, familial mutations account for less than 5% of AD cases. Since Abeta deposition is a key event in AD pathogenesis, we are interested in proteins that interact with APP and regulate its processing to Abeta. The LDL receptor-related protein (LRP/LRP1/CD91) is an endocytic receptor that is highly expressed in the brain; several studies have demonstrated that LRP interacts with APP and its expression in vitro and in vivo increases soluble Abeta.; In the first half of this thesis, we dissected the molecular mechanisms underlying the LRP-APP interaction to understand how LRP influences APP processing. By GST-pull down and ligand binding experiments, we identified two extracellular ligand binding domains of LRP that associate with APP and two intracellular motifs of LRP that interact with FE65, a protein that bridges APP and LRP in the cytoplasm. Next, we examined if LRP endocytosis influences APP localization. APP was retained at the cell surface with expression of endocytosis-deficient LRP mutants. These results defined regions of LRP that interact with APP and suggested a link between LRP endocytosis rate and APP trafficking.; In the second half of this thesis we investigated if APP interacts with LRP1B, a novel receptor that shares 59% amino acid identity with LRP and is also expressed in the brain. By co-immunoprecipitation, we found that LRP1B associates with APP. Expression of LRP1B increased APP cell surface localization and soluble APP secretion and decreased Abeta levels. These results are the first to identify LRP1B as an APP-binding partner that decreases Abeta production. Altogether our results indicate that LRP1B and LRP have opposing roles in APP processing and may ultimately influence the regulation of Abeta levels in both normal and pathological states such as AD.