Anti tau scFvs - new tools to better understand and treat Alzheimer's disease

• Applicant: Dr. Christina Ising
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Molecular and Cellular Neurology and Neuropathology
• Term: from 2015 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 288227629

Alzheimer's disease is the most common form of dementia, affecting about 35 million people worldwide with an increasing prevalence in our ageing society. The progression of Alzheimer's disease is associated with accumulation of amyloid-beta (Abeta) in amyloid plaques and tau in neurofibrillary tangles. Since Abeta aggregation precedes tau pathology, treatment strategies in the past years have focused on reducing amyloid plaque burden by active and passive immunization targeting Abeta. Although promising results have been achieved in mouse models of Alzheimer's disease (AD) this approach has not yet proven to be effective in clinical trials. Recent evidence suggests that accumulation of tau but not Abeta correlates with clinical symptoms in patients and that tau pathology spreads from cell-to-cell by a so far unknown mechanism. Dr. Holtzman's lab has previously shown that passive immunization with the in house made anti-tau antibody HJ8.5 decreased overall tau accumulation and slowed progression of the disease in a human tau P301S expressing transgenic mouse model of tauopathy. However, treatment of neurological diseases with antibodies remains difficult as a therapeutic strategy in humans due to only a small percentage of antibodies in the plasma being able to cross the blood-brain-barrier. Therefore, my project will focus on improving the feasibility of a treatment of AD and other tau related diseases with the HJ8.5 antibody utilizing a gene therapy approach targeting the central nervous system (CNS). To achieve this, single-chain fragment variable (scFv) antibodies, which consist of the variable region of the heavy and the light chain, connected by different peptide linkers, will be engineered and tested extensively in vitro and in vivo. scFvs have been shown to retain antigen-binding specificity and due to their small size yield good tissue penetration and can be easily packed into an adeno associated virus (AAV) for therapeutic delivery in the CNS. In addition to serving as a potential therapeutic agent, the scFvs will also be used as a biological tool to further elucidate the role of extracellular tau in tau propagation from cell to cell in vivo.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. David M. Holtzman