Brain Transit and Ameliorative Effects of Intranasally Delivered Anti-Amyloid-β Oligomer Antibody in 5XFAD Mice

Article type: Research Article

Authors: Xiao, Chun^{a; b} | Davis, Francesca J.^{a; b} | Chauhan, Balwantsinh C.^c | Viola, Kirsten L.^{d; e} | Lacor, Pascale N.^{d; e} | Velasco, Pauline T.^d | Klein, William L.^{d; e} | Chauhan, Neelima B.^{a; b; *}

Affiliations: [a] Neuroscience Research, Jesse Brown VA Medical Center, Chicago, IL, USA | [b] Department of Pediatrics, University of Illinois Hospital & Health Science System-Children's Hospital, University of Illinois at Chicago, Chicago, IL, USA | [c] Department of Biopharmaceutical Sciences, Roosevelt University, Schaumburg, IL, USA | [d] Department of Neurobiology, Northwestern University, Evanston, IL, USA | [e] Cognitive Neurology & Alzheimer's Disease Center, Northwestern University, Chicago, IL, USA

Correspondence: [*] Correspondence to: Neelima B. Chauhan, Ph.D., Jesse Brown VA Medical Center, 820 South Damen Avenue, Chicago, IL 60612, USA. Tel.: +1 312 569 7747; Fax: +1 312 569 8114; E-mail: [email protected].

Abstract: Alzheimer's disease (AD) is a global health crisis with limited treatment options. Despite major advances in neurotherapeutics, poor brain penetration due to the blood-brain barrier continues to pose a big challenge in overcoming the access of therapeutics to the central nervous system. In that regard, the non-invasive intranasal route of brain targeting is gaining considerable attention. The nasal mucosa offers a large surface area, rapid absorption, and avoidance of first-pass metabolism increasing drug bioavailability with less systemic side effects. Intranasal delivery is known to utilize olfactory, rostral migratory stream, and trigeminal routes to reach the brain. This investigation confirmed that intranasal delivery of oligomeric amyloid-β antibody (NU4) utilized all three routes to enter the brain with a resident time of 96 hours post single bolus intranasal administration, and showed evidence of perikaryal and parenchymal uptake of NU4 in 5XFAD mouse brain, confirming the intranasal route as a non-invasive and efficient way of delivering therapeutics to the brain. In addition, this study demonstrated that intranasal delivery of NU4 antibody lowered cerebral amyloid-β and improved spatial learning in 5XFAD mice.

Keywords: Alzheimer's immunotherapy, amyloid-β oligomer antibody, brain transit, cerebral amyloid-β immunocytochemistry, intranasal delivery, olfactory pathway, rostral migratory stream pathway, spatial acquisition learning, trigeminal pathway

DOI: 10.3233/JAD-122419

Journal: Journal of Alzheimer's Disease, vol. 35, no. 4, pp. 777-788, 2013