Targeting Tau Pathology in Alzheimer’s Disease: The Disease-Modifying Potential of Tau Immunotherapies
Introduction. Alzheimer’s disease (AD) is the most common form of dementia with an estimated 5.5 million cases in the US in 2017.1 Current treatments for AD alleviate symptoms, but do nothing to halt or reverse disease progression.2 Novel therapies are desperately needed in order to combat the pathological aggregation of tau protein and progressive cognitive decline characteristic of AD. Recent research suggests that tau oligomers play a vital role in tau-tau interactions leading to neurofibrillary pathology.3 Neutralization of tau oligomers presents a potential method of interfering in the AD process. DC8E8, a tau-specific monoclonal antibody (mAb), identified for its ability to inhibit tau oligomer formation by 84% in vitro,4 was utilized in the design of a novel active tau vaccine, AADvac1.5 This presentation discusses the disease-modifying potential of tau immunotherapies such as AADvac1. Methods. AADvac1 (Axon Neuroscience) was constructed using the synthetic tau peptide sequence 294KDNIKHVPGGGS305 derived from the tau oligomerization regulatory domain identified by DC8E8. Transgenic rats expressing human pathological tau protein in the brain and spinal cord received five subcutaneous injections of AADvac1 over six months. Serum antibody response was evaluated by ELISA. Sensorimotor function was assessed using Neuroscale tests. Brainstem samples from transgenic rats were immunostained and examined for tau pathology. Toxicology and safety studies using four times the intended human dose were conducted.5 Results. AADvac1 immunization induced serum antibodies with higher binding activity to pathological than physiological tau (P = 0.0028). The vaccine stimulated high IgG titers (GMT = 15,000), indicating a Th2 cell type response. Treatment reduced the presence of hyperphosphorylated tau monomers (P < 0.01) and tau oligomers (P < 0.05). Furthermore, AADvac1 immunization improved sensorimotor functions (P = 0.047) and reduced the number of rats with fully developed neurofibrillary pathology by 55%. Toxicology and safety pharmacological studies showed the vaccine to be well tolerated in tested species with no effects of toxicological relevance.5 Conclusions. The development of tau immunotherapy strategies represents a major stride forward for AD research. The robust immune response, reduced tau pathology, improved sensorimotor function, and favorable safety profiles of AADvac1 immunization lay the groundwork for a therapy with promising efficacy and modest side effects. This research inspires hope for a future AD treatment able to modify or even prevent disease altogether.
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- Alzheimer’s Association. 2016 Alzheimer’s disease facts and figures. Alzheimers Dement. 2016;12(4):459-509.
- Lasagna-Reeves CA, Castillo-Carranza DL, Sengupta U, et al. Alzheimer brain-derived tau oligomers propagate pathology from endogenous tau. Sci Rep. 2012;2:700.
- Kontsekova E, Zilka N, Kovacech B, Skrabana R, Novak M. Identification of structural determinants on tau protein essential for its pathological function: Novel therapeutic target for tau immunotherapy in Alzheimer’s disease. Alzheimers Res Ther. 2014;6(4):45.
- Kontsekova E, Zilka N, Kovacech B, Novak P, Novak M. First-in-man tau vaccine targeting structural determinants essential for pathological tau-tau interaction reduces tau oligomerisation and neurofibrillary degeneration in an Alzheimer’s disease model. Alzheimers Res Ther. 2014;6(4):44.