ABSTRACTAlzheimer’s disease (AD) is classified as a neurodegenerative disease which accounts for more than 60% of all cases of dementia. AD is characterized by two hallmark lesions: amyloid plaques and neurofibrillary tangles. According to the amyloid hypothesis, Aâ is the initiator of a cascade of reactions which causes Alzheimer at the end. But there is suggested that soluble oligomers of Aâ may play an early and critical role in neuronal dysfunction prior to overt plaque accumulation in the brain. Autopsy material from cases ranging from clinically non-demented to demented was prepared for electron microscopy to determine the cell association and ultra structural location of various forms of amyloid. Immunogold studies showed oligomeric Aâ over thin filaments extracellularly, representing pre-amyloid fibres, and within the cytoplasm and terminals of a subset of neurons. The observation of oligomeric Aâ within neuronal terminals suggests a role for intracellular soluble Aâ oligomers in neuronal dysfunction and plasticity.Recently a transgenic model for AD was derived that is characterized by the development of both plaques and tangles. These mice, referred to as the 3xTg-AD mice, harbour clinical mutations in the APP, PS1 and tau genes. In this model, plaques and tangles manifest in a progressive manner in AD-relevant brain regions such as the hippocampus, amygdala and cortex, with plaque developing prior to the neurofibrillary pathology. In our study we analyzed 3xTg-AD mice ranging from 6, 12, 18 and 30 months of age. Utilizing immunocytochemistry both at the light and electron microscopic level, we demonstrate various tau aggregates, including paired helical filaments. The tau modifications occur in a hierarchical manner, which first manifests with hyperphosphorylation and then proceed to mature tangles. The ultra structural analysis of these 3xTg-AD mice should enable us to detail the development of plaque and tangles and the interaction between them in the pathogenesis of this disorder.