Lauren Mitchell

 Introduction: Alzheimer’s Disease (AD) is a progressive, fatal and currently irreversible neurodegenerative disorder characterized by a decline in memory, cognition, then behavioral and motor function that accounts for 60-80% of all dementia cases in the US. AD care is going to cost upwards of $260 million in 2017 alone as 5.3+ million Americans over the age of 65 are living with AD and this number is predicted to climb to 13.8 million people by the year 2050¹. Unfortunately, this is due largely to that fact that are no treatments to stop or even slow the evolution of the disease right now. We now know that tau hyperphosphorylation (p-tau) and aggregation leading to neurofibrillary tangles (NFTs) play a large role in the pathogenesis of AD, in addition to b-amyloid (Ab) plaques.^2,3 Multiple therapeutic attempts to target Ab plaques have failed, but there has been an exciting turn towards targeting tau pathology recently, especially with immunotherapy. Methods: A study was conducted to identify cis p-tau as the earliest pathological tauopathy epitope, to test the use of anti-cis p-tau monoclonal antibodies (mAbs) to treat traumatic brain injury (TBI) and to prevent the progressive tauopathy causing the neurodegeneration seen in chronic traumatic encephalopathy (CTE) and AD. Cis and trans mouse mAbs were produced, isotopes were analyzed by ELISA and RCTs were conducted for administration to TBI mice. They also used immunofluorescence for multiple Abs (including cis mAb, trans mAb, tau tangle-related mAbs, oligomeric tau and T22 polyclonal Abs) and immunostaining analysis at different time intervals to assess the level of cis p-tau in mice brain with TBI and human brains with CTE.² Results: Large amounts of cis p-tau were found only 48 hours after TBI in mice and also in CTE human brains, indicating that cistauosis was induced before other tauopathy epitopes were present. Cis p-tau was found to spread, caused apoptosis after TBI and induced hypoxic stress. mAbs against cis p-tau used in mice studies were observed to eliminate cistauosis, prevent development and spread of tauopathy, and even restore some memory function and normal histophysiology after TBI.² Conclusions: The data from this study links TBI to CTE and AD, and cis p-tau was identified in the early stages of AD. Anti-cis p-tau mAb was found to prevent this phenomenon, blocking tauopathy progression and restoring many functional, structural and long-term potentiation (LTP) defects. This is the basis for tau immunotherapy and it could potentially provide more specific, targeted methods for the early diagnosis, prevention and therapy for these tauopathies, other neurodegenerative disorders and possibly even additional stress or hypoxia-induced conditions.²  While nothing has been approved yet, many are having success in early clinical trials and future research in this area looks promising.⁴

1. Alzheimer’s Association. 2017 Alzheimer’s Disease Facts and Figures. Alzheimers Dement 2017;13:325-373.
2. Kondo A, Shahpasand K, Mannix R, et al. Antibodies against early driver of neurodegeneration cis p-Tau blocks brain injury and tauopathy. Nature. 2015;523(7561):431-436.
3. Šimić G, Babić Leko M, Wray S, Harrington C, et al.Tau Protein Hyperphosphorylation and Aggregation in Alzheimer’s Disease and Other Tauopathies, and Possible Neuroprotective Strategies. Biomolecules. 2016; 6(1):6.
4. Godyń J, Jończyk J, Panek D, Malawska B. Therapeutic strategies for Alzheimer’s disease in clinical trials. Pharmacological Reports. 2016;68(1):127-138.