Virus-like particle (VLP)-based vaccine induces robust immunity against pathological tau and protects against tauopathy Nicole Maphis1,Julianne Peabody1, Erin Crossey, MD, PhD2, Shanya Jiang, PhD1, Fadi Jamaleddin Ahmad7, Maria Alvarez7, Amanda Yaney7, Yirong Yang, PhD4, Laurel Sillerud, PhD5, Colin Wilson6, Reed Selwyn, PhD6, Jonathan L. Brigman, PhD3, Judy L. Cannon, PhD1, David S. Peabody, PhD1, Bryce Chackerian, PhD1 and Kiran Bhaskar, PhD1,4* 1Department of Molecular Genetics and Microbiology, 3Department of Neurosciences, 4College of Pharmacy, 5Department of Neurology, 6Department of Radiology, 7School of Medicine, University of New Mexico, Albuquerque NM 87131 USA; 2Internal Medicine Residency Program, Department of Medicine, John A Burns School of Medicine, University of Hawaii, Honolulu HI 96813 USA *Corresponding author Alzheimer's disease (AD) is a progressive neurodegenerative disease clinically characterized by cognitive decline and likely mediated by the pathological aggregation of tau (pTau) as neurofibrillary tangles (NFTs). Current pTau-targeted immunotherapies have shown some success, however, they either employ passive immunotherapy, which requires repeated administration of a purified antigen over several administrations, or they involve the use of strong adjuvants, which could induce unwanted proinflammatory side effects. Here, we engineered a virus-like particle (VLP)-based pTau targeted vaccine by conjugating a human tau peptide phosphorylated at threonine 181 to Qβ VLPs (pT181-Qβ). We demonstrate that vaccination with pT181-Qβ is sufficient to induce robust anti-pT181 antibody titer, reduce soluble and insoluble hyperphosphorylated pTau, with no noticeable pro-inflammatory Th1 response, and prevent hippocampal atrophy and cognitive dysfunction in a 4-month-old rTg4510 mouse model of tauopathy. This is the first study to demonstrate the effectiveness of a VLP-based vaccine targeting pTau, which could serve as the basis for a highly efficacious, novel immunotherapy against tauopathies.
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