LRP1 Modulates APP Intraneuronal Transport and Processing in Its Monomeric and Dimeric State

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Low-density lipoprotein receptor-related protein 1 (LRP1) influences amyloid precursor protein (APP) processing, primarily through endocytosis.
• Recent findings suggest LRP1 retention in the ER reduces APP cell surface levels, decreasing Aβ secretion.

Purpose of the Study:

• To investigate the transport dynamics of LRP1 and APP in neurons.
• To elucidate the role of LRP1 in regulating APP cell surface localization and subsequent processing.

Main Methods:

• Live cell imaging in primary neurons.
• Biochemical and immunocytochemical analyses.
• LRP1 knockout studies in CHO cells and primary neurons.
• Analysis of cerebrospinal fluid in choroid plexus-specific LRP1 knockout mice.

Main Results:

• LRP1 and APP are transported in distinct fast axonal transport vesicles, with partial co-transport.
• LRP1 co-expression alters APP transport velocity, suggesting recruitment into specific vesicles.
• LRP1 deficiency increases cell surface APP, enhancing shedding by meprin β and ADAM10.
• LRP1 knockout leads to increased secretion of sAPP dimers over monomers in cerebrospinal fluid.

Conclusions:

• LRP1 functions as a sorting receptor for APP, controlling its cell surface presence.
• LRP1 regulates APP processing by ADAM10 and meprin β, with meprin β showing a preference for dimeric APP.