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Clinical Implications of Basic Neuroscience Research |

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

Kun Ping Lu, MD, PhD1,2; Asami Kondo, PhD1; Onder Albayram, PhD1; Megan K. Herbert, PhD1; Hekun Liu, PhD1,2; Xiao Zhen Zhou, MD1
[+] Author Affiliations
1Division of Translational Therapeutics, Department of Medicine and the Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
2Institute for Translational Medicine, Fujian Medical University, Fuzhou, China
JAMA Neurol. Published online September 19, 2016. doi:10.1001/jamaneurol.2016.2027
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ABSTRACT

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.

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Figure 1.
Cistauosis as an Early Druggable Mechanism in Alzheimer Disease (AD), Traumatic Brain Injury (TBI), and Chronic Traumatic Encephalopathy (CTE)

When tau is phosphorylated on the specific motif Thr231-Pro (ptau), it exists in 2 distinct conformations. The trans conformation promotes microtubule assembly critical for normal neuron function, whereas the cis conformation causes cistauosis, which includes the disruption of the axonal microtubule network and mitochondrial transport, spreading to other neurons, and leading to neuron death by apoptosis. The unique isomerase Pin1 protects against the development of tau-induced disease by accelerating cis to trans isomerization to prevent the accumulation of the pathogenic cis-ptau, notably in the axons of neurons. However, in AD, TBI, and CTE, Pin1 function is inhibited and cis-ptau is accumulated prominently in diffuse axons, thereby causing cistauosis and spreading axonal disruption with time, eventually leading to tau-mediated neurodegeneration and brain atrophy. Cistauosis and cis-ptau can be effectively and specifically neutralized by the cis-ptau monoclonal antibody (mAb), which also potently stops brain damage after TBI and prevents the late development of neurodegeneration, such as CTE, in animal models. LTP indicates long-term potentiation; P, Pro; and pT, phosphorylated Thr231.

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Figure 2.
A Model for Immunotherapy Targeting the Early Disease Driver Cis-Tau Phosphorylated on the Specific Motif Thr231-Pro (pTau)

Traumatic brain injury (TBI) induces cis-ptau in a dose-dependent manner. Whereas a single concussion (mild TBI) causes transient and modest cis-ptau induction that returns to the baseline within a couple of weeks, repetitive mild TBI or concussion, as seen in contact sports, or single moderate or severe TBI, as seen in exposure to blasts in the military or in road traffic crashes, causes persistent and robust cis-ptau induction, notably in diffuse axons within 12 to 24 hours after injury, long before any other known tau pathogenic changes. Cis-ptau causes cistauosis and spreads axonal disruption in the acute and chronic phases of TBI, which affects brain function and, years later, leads to widespread tau-mediated neurodegeneration and brain atrophy, a common feature of chronic traumatic encephalopathy (CTE), which are effectively blocked by treating TBI in mice with cis-ptau monoclonal antibody (mAb). Based on these results, we speculate that cis-ptau mAb may be used to develop diagnostic tests that could detect harmful levels of cis-ptau soon after TBI and also to develop a therapeutic antibody to halt brain damage after TBI, which would prevent the later development of progressive neurodegeneration, such as CTE. Whether and how TBI might cause Alzheimer disease remains to be determined. Arrows indicate the likelihood of developing CTE.

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