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

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