Tomoregulin (TMEFF2) Binds Alzheimer’s Disease Amyloid-β (Aβ) Oligomer and AβPP and Protects Neurons from Aβ-Induced Toxicity

Article type: Research Article

Authors: Hong, Hyun-Seok^{a; 1} | Maezawa, Izumi^{a; b; c} | Petrlova, Jitka^{d; 2} | Zhao, Xiao-Yan^e | C. Voss, John^d | Jin, Lee-Way^{a; b; c; *}

Affiliations: [a] Department of Pathology and Laboratory Medicine, University of California Davis Medical Center, Sacramento, CA, USA | [b] Alzheimer’s Disease Center, University of California Davis Medical Center, Sacramento, CA, USA | [c] M.I.N.D. (Medical Investigation of Neurodevelopmental Disorders) Institute, University of California Davis Medical Center, Sacramento, CA, USA | [d] Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, CA, USA | [e] Biologics Research-USIC, Bayer Healthcare Pharmaceuticals, San Francisco, CA, USA

Correspondence: [*] Correspondence to: Lee-Way Jin, MD, PhD, Department of Pathology and Laboratory Medicine, University of California Davis Medical Center, Sacramento, CA 95817, USA. Tel.: +1 916 703 0392; Fax: +1 916 703 0370; [email protected]

Note: [1] Present address: Medifron-DBT, Inc., Sandnaro 349, Danwon-gu, Ansan-si, Gyeonggi-do, Korea.

Note: [2] Present address: BMC B14, Department of Experimental Medical Science, Lund University, Lund, Sweden.

Abstract: Amyloid-β (Aβ) protein causes neurotoxicity and its abnormal aggregation into amyloid is a pathological hallmark of Alzheimer’s disease (AD). Cellular proteins able to interact with Aβ or its precursor, AβPP (amyloid-β protein precursor), may regulate Aβ production and neurotoxicity. We identified a brain-enriched type I transmembrane protein, tomoregulin (TR), that directly binds Aβ and Aβ oligomers (AβO). TR co-immunoprecipitated with Aβ and AβO in cultured cells and co-localized with amyloid plaques and intraneuronal Aβ 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 AβO with a high affinity (KD = 76.8 nM). Electron paramagnetic resonance spectroscopy also demonstrated a physical interaction between spin-labeled Aβ and the TR extracellular domain in solution. Furthermore, TR also interacted with AβPP and enhanced its cleavage by α-secretase. Both cellular expression of TR and application of recombinant TR extracellular domain protected N2a neurons from AβO-induced neuronal death. These data provide first evidence that neuronal and astrocytic expression of TR is intimately related to Aβ metabolism and toxicity, and could be neuroprotective through its direct interaction with Aβ and AβPP.

Keywords: Alzheimer’s disease, amyloid, binding, neuroprotection, neurotoxicity, tomoregulin

DOI: 10.3233/JAD-150318

Journal: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 731-743, 2015