EXTRACELLULAR-MATRIX INFLUENCES THE BIOGENESIS OF AMYLOID PRECURSOR PROTEIN IN MICROGLIAL CELLS

During axotomy studies, we discovered that the beta A4-amyloid precurs or protein (APP) participates in immune responses of the central nervo us system. Since microglia constitute the main immune effector cell po pulation of this response, we used the murine microglial cell line BV- 2 to analyze immune response-related APP expression. We show that inte raction of microglia with the extracellular environment, particularly components of the extracellular matrix, affects APP secretion as well as intracellular APP biogenesis and catabolism. Fibronectin enhanced A PP secretion and decreased the level of cellular mature transmembrane APP, whereas laminin and collagen caused a decrease in secretion and a n accumulation of cellular mature APP and APP fragments. Our results d emonstrate that APP plays a fundamental role in the regulation of micr oglial mobility, i.e. migration, initial target recognition, and bindi ng. The decrease in APP secretion and the concomitant increase in cell ular mature APP were accompanied by an accumulation of C-terminal APP fragments. Enrichment of APP and APP fragments is assumedly based on i nhibition of catabolic processes that is caused by a disorganization o f the actin microfilament network. These observations provide evidence that microglia, which are closely associated with certain amyloid dep osits in the brain of Alzheimer patients, can play a key role in initi al events of amyloidogenesis by initiating accumulation of APP and als o of amyloidogenic APP fragments in response to physiological changes upon brain injury.