Journal
JOURNAL OF ALZHEIMERS DISEASE
Volume 35, Issue 4, Pages 777-788Publisher
IOS PRESS
DOI: 10.3233/JAD-122419
Keywords
Alzheimer's immunotherapy; amyloid-beta oligomer antibody; brain transit; cerebral amyloid-beta immunocytochemistry; intranasal delivery; olfactory pathway; rostral migratory stream pathway; spatial acquisition learning; trigeminal pathway
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Funding
- Westside Institute for Science and Education
- Department of Pediatrics, University of Illinois at Chicago
- Children's Hospital of the University of Illinois, Chicago, IL
- Department of Biopharmaceutical Sciences, Roosevelt University, Schaumburg, IL
- National Institute of Health [AG039625, AG022547]
- Alzheimer's Association [ZEN-09-133875]
- Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Rehabilitation RD [B6285R]
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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-beta 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-beta and improved spatial learning in 5XFAD mice.
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