Anti-Amyloid-? 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-? protein (A?) in the brain is thought to be a causal event in Alzheimer's disease (AD). Immunotherapy targeting A? holds great promise for reducing A? in the brain. Here, we evaluated the efficacy and safety of anti-A? single-chain antibody (scFv59) delivery via recombinant adeno-associated virus (rAAV) on reducing A? deposits in an AD mouse model (TgA?PPswe/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 TgA?PPswe/PS1dE9 mice. rAAV5 was similarly injected into the ventricle of 10-month-old TgA?PPswe/PS1dE9 mice and 5 months later its efficacy and safety were evaluated. Immunoreactive A? deposits reduced in the hippocampus. A?42 levels in cerebrospinal fluid (CSF) tended to increase and the A?40 : 42 ratio decreased in CSF, suggesting that A?42 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 A?, caution for cerebrovascular effects should be exercised when rAAV-mediated anti-A? immunotherapy is applied.

SUBMITTER: Kou J 

PROVIDER: S-EPMC3560395 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature