Potential of the Antibody Against cis–Phosphorylated Tau in the Early Diagnosis, Treatment, and Prevention of Alzheimer Disease and Brain Injury

Alzheimer disease (AD) and chronic traumatic encephalopathy (CTE) share a common neuropathologic signature-neurofibrillary tangles made of phosphorylated tau-but do not have the same pathogenesis or symptoms. Although whether traumatic brain injury (TBI) could cause AD has not been established, CTE is shown to be associated with TBI. Until recently, whether and how TBI leads to tau-mediated neurodegeneration was unknown. The unique prolyl isomerase Pin1 protects against the development of tau-mediated neurodegeneration in AD by converting the phosphorylated Thr231-Pro motif in tau (ptau) from the pathogenic cis conformation to the physiologic trans conformation, thereby restoring ptau function. The recent development of antibodies able to distinguish and eliminate both conformations specifically has led to the discovery of cis-ptau as a precursor of tau-induced pathologic change and an early driver of neurodegeneration that directly links TBI to CTE and possibly to AD. Within hours of TBI in mice or neuronal stress in vitro, neurons prominently produce cis-ptau, which causes and spreads cis-ptau pathologic changes, termed cistauosis. Cistauosis eventually leads to widespread tau-mediated neurodegeneration and brain atrophy. Cistauosis is effectively blocked by the cis-ptau antibody, which targets intracellular cis-ptau for proteasome-mediated degradation and prevents extracellular cis-ptau from spreading to other neurons. Treating TBI mice with cis-ptau antibody not only blocks early cistauosis but also prevents development and spreading of tau-mediated neurodegeneration and brain atrophy and restores brain histopathologic features and functional outcomes. Thus, cistauosis is a common early disease mechanism for AD, TBI, and CTE, and cis-ptau and its antibody may be useful for early diagnosis, treatment, and prevention of these devastating diseases.