Abstract
With evidence supporting the prion-like spreading of extracellular tau as a mechanism for the initiation and progression of Alzheimerâs disease (AD), immunotherapy has emerged as a potential disease-modifying strategy to target tau. Many studies have proven effective to clear pathological tau species in animal models of AD, and several clinical trials using conventional immunotherapy with anti-tau native antibodies are currently active. We have previously generated a vectorized scFv derived from the conformation-dependent anti-tau antibody MC1, scFvMC1, and demonstrated that its intracranial injection was able to prevent tau pathology in adult tau mice. Here, we show that, in a prevention paradigm and in two different tau transgenic models (JNPL3 and P301S), a one-time intramuscular injection of AAV1-scFvMC1 generated a long-lasting peripheral source of anti-tau scFvMC1 and significantly reduced insoluble and soluble tau species in the brain. Moreover, our data showed that scFvMC1 was internalized by the microglia, in the absence of overt inflammation. This study demonstrates the efficacy of intramuscular delivery of vectorized scFv to target tau, and suggests a new potential application to treat AD and the other tauopathies.
Highlights
The microtubule-associated protein tau plays a physiological role in microtubule stabilization, axonal growth and cytoskeletal dynamics in neurons, but its aggregation characterizes several neurological diseases classified as tauopathies, including Alzheimerâs disease (AD) [1,2,3,4,5]
ScFvMC1 is detected in the brain homogenates upon intravenous injection of the purified Single chain variable fragment (scFv) We first asked whether Single chain variable fragment MC1 (scFvMC1) crosses the blood-brain barrier (BBB) and targets the brain [72, 73]
We have performed a proof-of concept experiment, testing BBB penetration via retroorbital IV injection of 100 Îźg of purified scFvMC1, either unlabeled (UNL) or infrared-conjugated (IR), in adult JNPL3 and P301S mice; a careful comparison was performed between scFvs and native MC1 variants, including saline as a negative control
Summary
The microtubule-associated protein tau plays a physiological role in microtubule stabilization, axonal growth and cytoskeletal dynamics in neurons, but its aggregation characterizes several neurological diseases classified as tauopathies, including Alzheimerâs disease (AD) [1,2,3,4,5]. ScFvs consist of the smallest functional antigenbinding domain of an antibody (Ab) exhibiting comparable antigen-binding affinity as the parent immunoglobulin, reduced size, improved pharmacokinetic in terms of tissue penetration and lack of an Fc receptormediated inflammatory response [46,47,48]. Due to their short systemic half-life in vivo [49, 50], in order to reach a sustained and long-lasting expression scFv are generally cloned in adeno associated viral vectors (AAVs) and delivered by one-time injections [34, 46, 47]. In this context, using AAVs is considered safer than LVs
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