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Objective  Progressive accumulation of  α ‐synuclein ( α ‐syn) has been associated with Parkinson's disease ( PD ) and Dementia with Lewy body ( DLB ). The mechanisms through which  α ‐syn leads to neurodegeneration are not completely clear; however, the formation of various oligomeric species have been proposed to play a role. Antibody therapy has shown effectiveness at reducing  α ‐syn accumulation in the central nervous system (CNS); however, most of these studies have been conducted utilizing antibodies that recognize both monomeric and higher molecular weight  α ‐syn. In this context, the main objective of this study was to investigate the efficacy of immunotherapy with single‐chain antibodies (sc FV s) against specific conformational forms of  α ‐syn fused to a novel brain penetrating sequence.    Method  We screened various sc FV s against  α ‐syn expressed from lentiviral vectors by intracerebral injections in an  α ‐syn tg model. The most effective sc FV s were fused to the cell‐penetrating peptide penetratin to enhance transport across the blood–brain barrier, and lentiviral vectors were constructed and tested for efficacy following systemic delivery intraperitoneal into  α ‐syn tg mice.    Result  Two sc FV s (D5 and 10H) selectively targeted different  α ‐syn oligomers and reduced the accumulation of  α ‐syn and ameliorated functional deficits when delivered late in disease development; however, only one of the antibodies (D5) was also effective when delivered early in disease development. These sc FV s were also utilized in an enzyme‐linked immunosorbent assay (ELISA) assay to monitor the effects of immunotherapy on  α ‐syn oligomers in brain and plasma.    Interpretation  The design and targeting of antibodies for specific species of  α ‐syn oligomers is crucial for therapeutic immunotherapy and might be of relevance for the treatment of Lewy body disease.

α ‐synuclein conformational antibodies fused to penetratin are effective in models of Lewy body disease