Early-onset forms of familial Alzheimer's disease (FAD) are usually caused by mutations in three known disease genes: the amyloid precursor protein (APP), and two presenilin genes (PSEN1 and PSEN2). APP is a single-transmembrane protein whose normal biological function is largely unknown. The congruence of FAD genetics and the presence of amyloid plaque pathology has focused attention on the APP proteolytic fragment Aβ, even while the normal function of APP remains largely unexplored. To fill this gap in our understanding, have studied the axon initial segment (AIS), a specialized region of a neuron that initiates an action potential.Immunocytochemistry of the two AIS scaffold proteins, Ankyrin G and βIV-spectrin, was performed on sections from the R1.40 mouse model of AD (B6.129-Tg(APPSw)40Btla/Mmjax) and from human frontal cortex samples (Braak Stage V-VI). We measured the length of the AIS and the intensity of their immunostaining. APP-overexpressing cultures will be recorded on the multielectrode-array (MEA) wells for electrophysiology studies RESULT: In frontal cortex of human AD cases and R1.40 mice, the AIS was shorter than in controls. In vitro, the AIS of cultured mouse neurons transfected with wild type or Swedish APP (APPSwe ) was shorter and also shifted distally along the axon. Both changes were greater with APPSwe than with wild type APP. Significantly, the addition of either Aβ oligomers or fibrils elicited no response. By transfecting neurons cultured in MEA wells, we showed that the observed shifts in the AIS altered neuronal firing patterns. We observed an overall decrease in mean spike number but not in spike amplitude.Our data suggest that the APP protein, but not the Aβ peptide, regulates neuronal activity through its effects on the position and length AIS. As APP is a neuronal stress response protein, our hypothesis is that age, trauma or genetic mutation leads to APP overexpression. While short term overexpression may protect against excitotoxicity, chronically elevated APP would permanently retard neuronal activity and serve as a substrate for dementia. This study argues for a reinterpretation of APP mutations as support for the role of the Aβ peptide in AD.