Filamentous actin (F-actin) is one of the major cytoskeleton proteins present in dendritic spines and it is an essential component for defining dendritic spine morphology. We have shown that synaptosomal F-actin levels were significantly decreased in APP/PS1 mice as early as one month of age. The molecular mechanisms involved in F-actin loss in synaptosomes, the underlying factors and the functional consequence involved needs to be elucidated. Synaptic neurotransmission and synaptic plasticity are dependent on the dynamic regulation of the actin through actin interacting and actin-modulating proteins. F-actin nanoarchitecture is regulated by several factors, such as reactive oxygen species and cofilin and others that are present in the dendritic spines. Yet, the key players and their role in synaptosomal F-actin organization remains unknown. Here, we characterized actin interactome from wild type and APP/PS1 male mice.