The role of the Alzheimer related Amyloid Precursor Protein Gene Family in the Developing and Adult Nervous System

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The role of APP as the precursor protein of the ß-amyloid peptide, which accumulates in extracellular plaques in Alzheimer¿s disease (AD), is well established and the secretases processing APP constitute major therapeutic targets. By contrast, its physiological function and the question of whether a loss of these functions contributes to pathogenesis remains largely unresolved. APP is a member of a larger gene family including the closely related APP-like proteins APLP1 and APLP2. To address the physiological functions of the APP gene family directly, we had previously generated APLP2-/-/APLP1-/-- and APLP2-/-/APP-/-- mice that die perinatally, while APLP1-/-/APP-/--mice and single mutants were viable. Recently, we generated triple mutant mice lacking all three APP/APLP family members which also died shortly after birth. Whereas lethal double mutants showed no apparent morphological abnormalities, the brains of triple mutants displayed a phenotype resembling human type II lissencephaly with ectopic clusters of neuroblasts that had migrated through the basal lamina and pial membrane, indicating a role of APP/APLPs in neruonal adhesion and/or migration. Collectively, our data demonstrate that APP/APLPs are essential for normal brain development and early postnatal survival. However, this perinatal lethality, precludes the analysis of proposed functions in the postnatal and adult, aging nervous system. Moreover, the underlying mechanism of lethality is presently unknown. The aim of the current project is thus to circumvent early lethality by two complementary approaches. To this end, we intend to (A) generate conditional null mutants using a tetracycline regulated genetic switch (tet-off) to downregulate APP/APLP expression postnatally. Secondly (B), we intend to ablate APP expression in a neuron-specific manner, either already during development in neural progenitor cells, or in postmitotic neurons postnatally. This approach will unravel whether lethality is, as hypothesized, due to compromised functions within the nervous system or due to unrelated defects in peripheral organs. We intend to characterize these mutant lines of mice with regard to the morphological and functional maturation of the nervous system, in particular synaptogenesis, neuronal plasticity, sensorimotor development, as well as learning and memory. Understanding the physiological functions of APP and its homologous in the adult and aging nervous system will be essential to unravel the misregulation and pathogenic mechanisms that lead to Alzheimer¿s disease.