Regulation of Lateral Mobility of Amyloid Precursor Protein by an Alzheimer s Disease Risk Gene Picalm

Abstract

Amyloid Precursor Protein (APP) is implicated in several functions in neurons, but the altered processing of APP in synapses holds a key to understanding the onset of the molecular progression of Alzheimer s Disease (AD). Proteolytic processing of APP through sequential activity of and#946;-secretase and and#947;-secretase or Amyloidogenic processing results in formation of amyloid-beta (Aand#946;) peptides. The onset of AD possibly arises due to increase in production of Aand#946; peptides or as an effect of impaired clearance of Aand#946; peptides from the brain. Years of research has been invested in identifying the proteolytic processing of APP and how the shift in concentration of Aand#946; peptides leads to irreversible changes in molecular progression. But this knowledgebase becomes vague when we try to address finer aspects of the regulation of these processes at synaptic or molecular levels. Recent evidence indicates that APP is segregated in highly enriched regions of about 100 nm diameter on neuronal and synaptic membranes. The molecular density of APP within such nanodomains is controlled by lateral diffusion of APP at a millisecond time scale. These characteristics also vary across nanodomains present in functional domains of synapses like postsynaptic density, cytomatrix of active zone or even the endocytic zone. Thus, molecules which interact with APP in these regions can control its lateral diffusion and then in turn modulate the processing of APP through amyloidogenic pathway. Several genes have been characterized as risk factors for AD. Strikingly few risk factors are involved in clathrin mediated endocytosis (CME) along with other factors which are directly involved in the modulation of APP or its processing. A clathrin adaptor protein, Phosphotidyl Inositol Binding Clathrin Adaptor Protein (PICALM) has been found to be one of these risk factors. To characterize the association of PICALM to APP we followed a combination of immunolabelling, and high-resolution microscopy to map their localization in different neuronal compartments...