Extracellular Release of ILEI/FAM3C and Amyloid-β Is Associated with the Activation of Distinct Synapse Subpopulations

Article type: Research Article

Authors: Nakano, Masaki^a | Mitsuishi, Yachiyo^a | Liu, Lei^{a; 1} | Watanabe, Naoki^a | Hibino, Emi^a | Hata, Saori^{b; c} | Saito, Takashi^{d; e} | Saido, Takaomi C.^d | Murayama, Shigeo^{f; 2} | Kasuga, Kensaku^g | Ikeuchi, Takeshi^g | Suzuki, Toshiharu^b | Nishimura, Masaki^{a; *}

Affiliations: [a] Molecular Neuroscience Research Center, Shiga University of Medical Science, Shiga, Japan | [b] Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Hokkaido, Japan | [c] Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan | [d] Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Saitama, Japan | [e] Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Science, Nagoya, Japan | [f] Department of Neurology and Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan | [g] Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan

Correspondence: [*] Correspondence to: Masaki Nishimura, Molecular Neuroscience Research Center, Shiga University of Medical Science, Shiga, 520 2192, Japan. Tel.:+81 77 548 2328; Fax:+81 77 5482210; E-mail: mnishimu@belle.shiga-med.ac.jp.

Note: [1] Present address: Ann Romney Center for Neurologic Diseases,Brigham andWomen’s Hospital, Harvard Medical School, Boston, MA, USA.

Note: [2] Present address: Brain Bank for Neurodevelopmental, Neurological and Psychiatric Disorders, United Graduate School of Child, Development, Osaka University, Osaka, Japan.

Abstract: Background:Brain amyloid-β (Aβ) peptide is released into the interstitial fluid (ISF) in a neuronal activity-dependent manner, and Aβ deposition in Alzheimer’s disease (AD) is linked to baseline neuronal activity. Although the intrinsic mechanism for Aβ generation remains to be elucidated, interleukin-like epithelial-mesenchymal transition inducer (ILEI) is a candidate for an endogenous Aβ suppressor. Objective:This study aimed to access the mechanism underlying ILEI secretion and its effect on Aβ production in the brain. Methods:ILEI and Aβ levels in the cerebral cortex were monitored using a newly developed ILEI-specific ELISA and in vivo microdialysis in mutant human Aβ precursor protein-knockin mice. ILEI levels in autopsied brains and cerebrospinal fluid (CSF) were measured using ELISA. Results:Extracellular release of ILEI and Aβ was dependent on neuronal activation and specifically on tetanus toxin-sensitive exocytosis of synaptic vesicles. However, simultaneous monitoring of extracellular ILEI and Aβ revealed that a spontaneous fluctuation of ILEI levels appeared to inversely mirror that of Aβ levels. Selective activation and inhibition of synaptic receptors differentially altered these levels. The evoked activation of AMPA-type receptors resulted in opposing changes to ILEI and Aβ levels. Brain ILEI levels were selectively decreased in AD. CSF ILEI concentration correlated with that of Aβ and were reduced in AD and mild cognitive impairment. Conclusion:ILEI and Aβ are released from distinct subpopulations of synaptic terminals in an activity-dependent manner, and ILEI negatively regulates Aβ production in specific synapse types. CSF ILEI might represent a surrogate marker for the accumulation of brain Aβ.

Keywords: Alzheimer’s disease, amyloid-β, ILEI, neurotransmitter receptor, synapse

DOI: 10.3233/JAD-201174

Journal: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 159-174, 2021