Tau Immunotherapy and Imaging

Abstract

Disappointing findings from recent phase III trials on amyloid-β (Aβ) immunotherapy for Alzheimer's disease (AD) have shifted the focus of such treatments to the tau protein. As tau pathology correlates better with the degree of dementia than Aβ plaque burden, it is a more attractive target once cognitive impairments are evident, while Aβ therapies may be better suited for the presymptomatic phase of the disease. Over 12 years ago, we initiated a tau immunotherapy program, seeking to alleviate the functional impairments associated with tau lesions in tauopathies. We have reported that various active and passive tau immunizations diminish tau pathology and improve function, including cognition, in different mouse models. Both extra- and intracellular pathways are likely involved. The antibodies may block the spread of tau pathology via microglial phagocytosis of the antibody-tau complex and facilitate lysosomal tau clearance in neurons after endosomal uptake. We have observed such antibody internalization following intracarotid injection in mice and in various culture models. These include brain slices and primary neurons from tangle mice as well as human neuroblastoma cell lines. Antibody targeting of different intracellular protein aggregates, including α-synuclein, Aβ and superoxide dismutase has been reported by others. Now, several laboratories have confirmed and extended our findings using various active and passive tau immunizations in different models, thereby clearly establishing the feasibility of this approach for clinical trials. We are also working on imaging approaches to monitor tau pathology, its consequences and the efficacy of treatments. Dire need exists for such diagnostic methods for tauopathies. Overall, therapies and diagnostic tools targeting tau pathology have a great potential for AD and other tauopathies.

Alzheimer’s disease AdvaxCpG- adjuvanted MultiTEP-based dual and single vaccines induce high-titer antibodies against various forms of tau and Aβ pathological molecules

“…As mentioned above, the difference in the timing of Aβ and tau accumulation 34 and their different roles in the onset and progression of AD, suggest that sequential vaccinations with Aβ and tau vaccines, or even combined vaccine against both molecules might represent the most effective AD approach. In particular, the same vaccine platform could be used to both prevent the onset of AD [41][42][43][44] , and also slow down development of tauopathy-associated dementia 32,[45][46][47][48][49][50][51] . In order to utilize such an approach we have developed three MultiTEP platform-based vaccines targeting Aβ , tau or both molecules simultaneously.…”

Differential Regulation of Resolution in Inflammation induced by Amyloid-β42 and Lipopolysaccharides in Human Microglia

“…In addition to a therapy based on reduction of Aβ, reducing the hyperphosphorylation of tau represents another major therapeutic target for AD. Strategies targeting tau pathology include vaccination, anti-tau aggregation [58], and the targeting of kinases that are involved in tau phosphorylation [59].…”

Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy

“…Such tangles are also a hallmark of AD and related neurodegenerative disorders, collectively termed tauopathies 13 , 14 . Tauopathy spreads in brains 15 - 19 and is reduced by immunotherapy against tauopathy epitopes 20 - 22 . However, since little tauopathy is detectable acutely or subacutely after TBI in humans and mice 5 , 7 - 9 , 23 - 25 , whether tauopathy is a cause or consequence of post-traumatic neurodegeneration is unknown.…”