Alzheimer's disease (AD) is characterized by the formation of amyloid plaques and cerebrovascular amyloid deposits, the principal component of which is the -4kDa amyloid peptide. Abeta is derived from a large transmembrane precursor, the amyloid precursor protein (betaAPP), physiological functions of which remains to be elucidated. Previous studies suggest that the distribution of betaAPP between the trans-Golgi network (TGN) and cell surface has a direct influence upon the generation of Aa This phenomenon makes delineation of the mechanisms responsible for regulating aAPP trafficking from the TGN relevant to understanding the pathogenesis of AD. Recent evidence from several groups including ours suggests a role for presenilin-1 (PS1) in regulating intracellular trafficking/maturation, within the secretory pathways of select proteins including betaAPP, nicastrin, TrkB and a PSI-binding protein (ICAM-5/telecephalin). Using a cell-free vesicle trafficking reconstitution system derived from neuroblastoma cells, we demonstrated that, PS1 regulates the biogenesis of betaAPP-containing vesicles from the trans-Golgi Network (TGN) and the endoplasmic reticulum (ER). PS1 deficiency or the expression of loss-of-function variants leads to robust vesicle formation, concomitant with increased maturation and or cell surface accumulation of betaAPP. In contrast, release of vesicles containing aAPP is impaired in FAD-linked PS1 mutant cells, resulting in reduced betaAPP delivery to the cell surface. Moreover, diminution of surface betaAPP is profound at axonal terminals in neurons expressing a PS1 FAD variant. These results suggest an alternative mechanism by which FAD-linked PS1 variants modulate aAPP processing along a pathologic, amyloidogenic pathway. Therefore, the objective of this proposal is to address the cellular mechanisms underlying PS1 regulation of aAPP trafficking as well as to assess physiological and pathological implications of this regulated axonal transport of aAPP in neuronal functions. Based on these premise, the specific aims for the project are as follows: 1) To determine whether recruitment and (in)activation of certain cytosolic factors affects PS-1 regulated betaAPP trafficking. 2) To assess the correlation of PSI-regulated axonal transport of betaAPP with its neuronal functions such as neurite outgrowth and synaptic plasticity. 3) To elucidate the effects of identified cytosolic factors on these neuronal functions via modulation of PSI-regulated betaAPP trafficking.