title: 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.
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.
authors.affiliation: Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, IL 61656, USA.
authors.forename: Jinghong
authors.initials: J
authors.lastname: Kou
authors.forename: HongDuck
authors.initials: H
authors.lastname: Kim
authors.forename: Abhinandan
authors.initials: A
authors.lastname: Pattanayak
authors.forename: Min
authors.initials: M
authors.lastname: Song
authors.forename: Jeong-Eun
authors.initials: JE
authors.lastname: Lim
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Taguchi
authors.forename: Sudhir
authors.initials: S
authors.lastname: Paul
authors.forename: John R
authors.initials: JR
authors.lastname: Cirrito
authors.forename: Selvarangan
authors.initials: S
authors.lastname: Ponnazhagan
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Fukuchi
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000276:immunology*; D016564:Amyloid beta-Protein Precursor; D058227:Amyloidogenic Proteins / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D015703:Antigens, CD; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002461:Cell Line, Transformed; D002543:Cerebral Hemorrhage / Q000139:chemically induced*; D000229:Dependovirus / Q000502:physiology; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007167:Immunotherapy; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053764:Presenilin-1; D057127:Single-Chain Antibodies / Q000009:adverse effects*; D014161:Transduction, Genetic; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D058227:Amyloidogenic Proteins; D015703:Antigens, CD; D005904:Glial Fibrillary Acidic Protein; C508853:PSEN1 protein, human; D053764:Presenilin-1; D057127:Single-Chain Antibodies