Previous work in our and other laboratories has demonstrated neuronal cell toxicity related to intracellular Aβ deposition and its aggregation into oligomers. The accumulation of intraneuronal Aβ oligomers is associated with pathological alterations in transgenic APP mouse and human Alzheimer's disease (AD) brains. Here we investigate the non-Aβ components of intracellular oligomers, under the hypothesis that these components may regulate the oligomer formation and therefore affect the Aβ-related toxicity seen in AD. Intracellular Aβ oligomers formed in neuroblastoma MC65 and N2a-APP cells were isolated by immunoaffinity chromatography and size exclusion chromatography. The protein components were then identified by mass spectrometry. The identified proteins were then confirmed for their interaction with Aβ using co-immunoprecipitation. A transmembrane protein with epidermal growth factor-like and follistatin-like modules in the extracellular domain, called tomoregulin-2 (TMEFF2), was identified from isolated intracellular Aβ oligomers. Using a TMEFF2-specific antibody, we co-immunoprecipitated components of Aβ oligomers including the Aβ dimers and trimers from cell lysates, confirming its interaction with Aβ oligomers. In addition, TMEFF2 was also co-immunoprecipitated with the β-amyloid precursor protein (APP). Overexpression of TMEFF2 in neuroblastoma cells increased the secretion of APP, while downregulation of TMEFF2 by RNA interference decreased the secretion of APP. TMEFF2 is a non-Aβ component of intraneuronal Aβ oligomers, and may also regulate APP metabolism. Interestingly, TMEFF2 was found extensively in Alzheimer's disease plaques (J Neurochem, 2006, 98:34), suggesting that it may regulate Aβ amyloidosis in AD, including the intraneuronal Aβ aggregation process.