Alzheimer's disease (AD) is characterized by a substantial degeneration of pyramidal neurons and the appearance of neuritic plaques and neurofibrillary tangles. Here we present a novel transgenic mouse model, APPSLPS1KI that closely mimics the development of AD-related neuropathological features including a significant hippocampal neuronal loss. This transgenic mouse model carries M233T/L235P knocked-in mutations in presenilin-1 and overexpresses mutated human β-amyloid (Aβ) precursor protein. Aβx-42 is the major form of Aβ species present in this model with progressive development of a complex pattern of N-truncated variants and dinners, similar to those observed in AD brain. At 10 months of age, an extensive neuronal loss (>50%) is present in the CA1/2 hippocampal pyramidal cell layer that correlates with strong accumulation of intraneuronal Aβ and thioflavine-S-positive intracellular material but not with extracellular Aβ deposits. A strong reactive astrogliosis develops together with the neuronal loss. This loss is already detectable at 6 months of age and is PS1KI gene dosage-dependent. Thus, APPSLPS1KI mice further confirm the critical role of intraneuronal Aβ42 in neuronal loss and provide an excellent tool to investigate therapeutic strategies designed to prevent AD neurodegeneration.