Anti-Amyloid-β Single-Chain Antibody Brain Delivery Via AAV Reduces Amyloid Load But May Increase Cerebral Hemorrhages in an Alzheimer's Disease Mouse Model

Article type: Research Article

Authors: Kou, Jinghong^a | Kim, HongDuck^b | Pattanayak, Abhinandan^a | Song, Min^{a; c} | Lim, Jeong-Eun^a | Taguchi, Hiroaki^d | Paul, Sudhir^d | Cirrito, John R.^e | Ponnazhagan, Selvarangan^f | Fukuchi, Ken-ichiro^{a; *}

Affiliations: [a] Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, IL, USA | [b] Department of Environmental Health Science, New York Medical College, Valhalla, NY, USA | [c] Department of Medical Genetics, Third Military Medical University, Chongqing, PR China | [d] Chemical Immunology Research Center, Department of Pathology and Laboratory Medicine, University of Texas, Houston Medical School, Houston, TX, USA | [e] Department of Neurology and Hope Center for Neurological Disorders, Washington, University School of Medicine, St. Louis, MO, USA | [f] Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, USA

Correspondence: [*] Correspondence to: Ken-ichiro Fukuchi, Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, P.O. Box: 1649, Peoria, IL 61656, USA. Tel.: +309 671 8545; Fax: +309 671 8403; E-mail: kfukuchi@uic.edu.

Abstract: Accumulation of amyloid-β protein (Aβ) in the brain is thought to be a causal event in Alzheimer's disease (AD). Immunotherapy targeting Aβ holds great promise for reducing Aβ in the brain. Here, we evaluated the efficacy and safety of anti-Aβ single-chain antibody (scFv59) delivery via recombinant adeno-associated virus (rAAV) on reducing Aβ deposits in an AD mouse model (TgAβPPswe/PS1dE9). First, delivery of scFv59 to the brain was optimized by injecting rAAV serotypes 1, 2, and 5 into the right lateral ventricle. Symmetrical high expression of scFv59 was found throughout the hippocampus and partly in the neocortex in both hemispheres via rAAV1 or rAAV5, while scFv59 expression via rAAV2 was mostly limited to one hemisphere. rAAV1, however, induced apoptosis and microglial activation but rAAV5 did not. Therefore, rAAV5 was selected for therapeutic scFv59 delivery in TgAβPPswe/PS1dE9 mice. rAAV5 was similarly injected into the ventricle of 10-month-old TgAβPPswe/PS1dE9 mice and 5 months later its efficacy and safety were evaluated. Immunoreactive Aβ deposits reduced in the hippocampus. Aβ42 levels in cerebrospinal fluid (CSF) tended to increase and the Aβ40 : 42 ratio decreased in CSF, suggesting that Aβ42 was relocated from the parenchyma to CSF. Hemorrhages associated with a focal increase in blood vessel amyloid were found in the brain. While immunotherapy has great potential for clearing cerebral Aβ, caution for cerebrovascular effects should be exercised when rAAV-mediated anti-Aβ immunotherapy is applied.

Keywords: Adeno-associated virus, Alzheimer's disease, amyloid, cerebral hemorrhage, immunotherapy, single-chain antibodies

DOI: 10.3233/JAD-2011-110230

Journal: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 23-38, 2011