First Author | Hong HS | Year | 2015 |
Journal | J Alzheimers Dis | Volume | 48 |
Issue | 3 | Pages | 731-43 |
PubMed ID | 26402097 | Mgi Jnum | J:309831 |
Mgi Id | MGI:6709435 | Doi | 10.3233/JAD-150318 |
Citation | Hong HS, et al. (2015) Tomoregulin (TMEFF2) Binds Alzheimer's Disease Amyloid-beta (Abeta) Oligomer and AbetaPP and Protects Neurons from Abeta-Induced Toxicity. J Alzheimers Dis 48(3):731-43 |
abstractText | Amyloid-beta (Abeta) protein causes neurotoxicity and its abnormal aggregation into amyloid is a pathological hallmark of Alzheimer's disease (AD). Cellular proteins able to interact with Abeta or its precursor, AbetaPP (amyloid-beta protein precursor), may regulate Abeta production and neurotoxicity. We identified a brain-enriched type I transmembrane protein, tomoregulin (TR), that directly binds Abeta and Abeta oligomers (AbetaO). TR co-immunoprecipitated with Abeta and AbetaO in cultured cells and co-localized with amyloid plaques and intraneuronal Abeta in the 5xFAD AD mouse model. TR was also enriched in astrocytic processes reactive to amyloid plaques. Surface plasmon resonance spectroscopy studies showed that the extracellular domain of TR binds to AbetaO with a high affinity (KD = 76.8 nM). Electron paramagnetic resonance spectroscopy also demonstrated a physical interaction between spin-labeled Abeta and the TR extracellular domain in solution. Furthermore, TR also interacted with AbetaPP and enhanced its cleavage by alpha-secretase. Both cellular expression of TR and application of recombinant TR extracellular domain protected N2a neurons from AbetaO-induced neuronal death. These data provide first evidence that neuronal and astrocytic expression of TR is intimately related to Abeta metabolism and toxicity, and could be neuroprotective through its direct interaction with Abeta and AbetaPP. |