MultiTEP platform-based DNA epitope vaccine targeting N-terminus of tau induces strong immune responses and reduces tau pathology in THY-Tau22 mice.

BACKGROUND: By the time clinical symptoms of Alzheimer's disease (AD) manifest in patients there is already substantial tau pathology in the brain. Recent evidence also suggests that tau pathology can become self-propagating, further accelerating disease progression. Over the last decade several groups have tested the efficacy of protein-based anti-tau immunotherapeutics in various animal models of tauopathy. Here we report on the immunological and therapeutic potency of the first anti-tau DNA vaccine based on the MultiTEP platform, AV-1980D, in THY-Tau22 transgenic mice. METHODS: Starting at 3months of age, mice were immunized intramuscularly with AV-1980D vaccine targeting a tau B cell epitope spanning aa2-18 followed by electroporation (EP). Humoral and cellular immune responses in vaccinated animals were analyzed by ELISA and ELISpot, respectively. Neuropathological changes in the brains of experimental and control mice were then analyzed by biochemical (WB and ELISA) and immunohistochemical (IHC) methods at 9months of age. RESULTS: EP-mediated AV-1980D vaccinations of THY-Tau22 mice induced activation of Th cells specific to the MultiTEP vaccine platform and triggered robust humoral immunity response specific to tau. Importantly, no activation of potentially harmful autoreactive Th cell responses specific to endogenous tau species was detected. The maximum titers of anti-tau antibodies were reached after two immunizations and remained slightly lower, but steady during five subsequent monthly immunizations. Vaccinations with AV-1980D followed by EP significantly reduced total tau and pS199 and AT180 phosphorylated tau levels in the brains extracts of vaccinated mice, but produced on subtle non-significant effects on other phosphorylated tau species. CONCLUSIONS: These data demonstrate that MultiTEP-based DNA epitope vaccination targeting the N-terminus of tau is highly immunogenic and therapeutically potent in the THY-Tau22 mouse model of tauopathy and indicate that EP-mediated DNA immunization is an attractive alternative to protein-based adjuvanted vaccines for inducing high concentrations of anti-tau antibodies.

Concise review: Can stem cells be used to treat or model Alzheimer's disease?

Alzheimer's disease (AD) is the leading cause of age-related dementia, affecting over 5 million people in the U.S. alone. AD patients suffer from progressive neurodegeneration that gradually impairs their memory, ability to learn, and carry out daily activities. Unfortunately, current therapies for AD are largely palliative and several promising drug candidates have failed in recent clinical trials. There is therefore an urgent need to improve our understanding of AD pathogenesis, create innovative and predictive models, and develop new and effective therapies. In this review, we will discuss the potential of stem cells to aid in these challenging endeavors. Because of the widespread nature of AD pathology, cell-replacement strategies have been viewed as an incredibly challenging and unlikely treatment approach. Yet recent work shows that transplantation of neural stem cells (NSCs) can improve cognition, reduce neuronal loss, and enhance synaptic plasticity in animal models of AD. Interestingly, the mechanisms that mediate these effects appear to involve neuroprotection and trophic support rather than neuronal replacement. Stem cells may also offer a powerful new approach to model and study AD. Patient-derived induced pluripotent stem cells, for example, may help to advance our understanding of disease mechanisms. Likewise, studies of human embryonic and NSCs are helping to decipher the normal functions of AD-related genes; revealing intriguing roles in neural development.