Studying a Type of Tau Protein that Specifically Aggregates in Alzheimer’s

Zhuohao He, PhD
University of Pennsylvania (Philadelphia, PA)
Year Awarded:
Grant Duration:
July 1, 2018 to June 30, 2021
Alzheimer's Disease
Award Amount:
Grant Reference ID:
Award Type:
Award Region:
US Northeastern
Zhuohao He, PhD

Studying an Alzheimer's disease-Specific Tau Strain


Alzheimer’s disease (AD) is correlated with the aggregation of tau protein, which also deposits in several other neurodegenerative diseases. The AD-specific tau deposit has recently been identified and recapitulated in animal models by our laboratory, but the properties of such AD-specific tau deposits are still largely unclear. This project is aimed at characterizing such AD-specific tau deposits, with the hope of developing an AD diagnosis method and potentially new treatment approaches. 


Alzheimer’s disease (AD) is correlated with the aggregation of protein tau, which also forms deposits in several other neurodegenerative diseases. This aim of this project is to characterize AD-specific tau deposits. To achieve this, we will first characterize the differences between such AD-specific tau deposit and the other commonly recognized tau deposits localized in neuronal cell bodies. We will generate a more human-relevant mouse model expressing all the human-version tau protein in the mouse brains. Then using the mouse models as well as AD postmortem brain tissues, we will biochemically extract each type of tau deposit, respectively, and compare their protein conformation and their potencies to induce disease-related tau accumulation. We also will aim to generate an antibody to recognize such AD-specific abnormal tau deposits, and try to examine the correlation between the AD-specific tau deposits from patients’ cerebrospinal fluid and the patients’ AD stages, with the hope to develop an AD diagnostic method.

The completion of the proposed studies will help us understand the initial tau deposit and spreading processes in AD pathogenesis. The antibodies generated in the proposal will be the first in the AD research field that specifically target the AD-specific tau deposits, and will provide the AD research community with useful tools to study the AD pathogenesis, as well as to develop both diagnostic methods and immunotherapy approaches for treating AD patients at early stages.

The innovative aspect of this proposal is the use of our newly established AD mouse models that can respectively recapitulate AD-specific or generally recognized neuronal cell body tau deposits, allowing us to investigate their respective roles in AD progression. Creating the mouse tools that express all the human version tau will make our study more relevant.

About the Researcher

I am currently a senior research investigator at the Center for Neurodegenerative Disease Research, University of Pennsylvania, with more than 12 years’ experience researching central nervous system (CNS) diseases. Following completion of my undergraduate degree in Biotechnology at Wuhan University, China, I received my PhD training at the Institute of Neuroscience, Chinese Academy of Sciences, where I studied the roles of Ca2+ signaling mediated by a group of Ca2+ permeable ion channels in CNS under physiological and pathological conditions. Following the completion of my PhD in 2012, I did postdoctoral research with Drs. Virginia Lee and John Trojanowski at University of Pennsylvania, where I studied Alzheimer’s disease (AD) and related neurodegenerative diseases from the perspective of misfolding tau proteins. I have developed several unique pathological-relevant AD mouse models, and also proposed a novel mechanism explaining how pathological tau may spread across the AD brains with the help of amyloid beta (Aβ) plaques. These works will provide new tools and open new avenues for researchers in the field to identify new targets and develop new treatments for patients with AD. In 2018, I was promoted to be a senior research investigator, and I will lead my independent research with a long-term career goal to develop diagnostic methods and treatments for patients with early stages of AD and related diseases.  

Personal Story

My interests in neurodegenerative diseases were first raised during my college years when my grandma showed dementia after she had a stroke. At that moment, the doctors didn’t tell us what kind of disease my grandma suffered from. As her disease progressed, she gradually lost the ability to communicate and wasn’t able to take care of herself, which brought great sadness and burden to our whole family. I was eager to know why the disease made my lovely grandma change into a person who did not recognize her lovely grandson, with this occurring within just a few years. Since then, I have been determined to use my intelligence and effort throughout my career find the answer. However, when I graduated, I had little knowledge about neuroscience, so I decided to pursue my long term goal step-by-step, and initially by studying some fundamental neuroscience questions at the Institute of Neuroscience, Chinese Academy of Sciences, the best place to study neuroscience in China.  

After obtaining my PhD degree in 2012, I followed my initial dream and I came to the USA to conduct my postdoctoral research on neurodegenerative diseases with Drs. Virginia Lee and John Trojanowski. Their labs’ enriched resources gave me a unique training and broadened my vision on neurodegenerative disease studies. There I studied AD and related diseases from the perspective of misfolding tau protein, a most common pathology in a group of neurodegenerative diseases. I developed a unique AD mouse model that recapitulates all major types of AD pathologies existing in human AD brains, and provided evidence for the first time suggesting that pathological tau is initially deposited in the abnormal neurites around Aβ plaques, as neuritic plaques, instead of depositing in the cell body as neurofibrillary tangles. This study pointed out more research attention should be paid to neuritic plaque tau that extensively and specifically exists in AD brains. However, the properties of such AD-specific pathology are unclear. Since 2018, I have been promoted to the position of Senior Research Investigator at the Center for Neurodegenerative Disease Research, University of Pennsylvania, and I plan to lead an independent effort to study and verify whether AD-specific tau pathology is the disease driver. To achieve this, we will also generate tools, including specific antibodies, to study such AD-specific tau pathology. The results will lay the basis for the potential development of new AD diagnostic methods and treatment approaches. 
As a junior investigator, and especially as a foreign researcher, it is very hard to get the initial support here. The generous support from the BrigthFocus donors will definitely help me to make a better transition into becoming an independent investigator, and start my own academic career in the field of AD research.


Darwich NF, Phan JM, Kim B, Suh E, Papatriantafyllou JD, Changolkar L, Nguyen AT, O'Rourke CM, He Z, Porta S, Gibbons GS, Luk KC, Papageorgiou SG, Grossman M, Massimo L, Irwin DJ, McMillan CT, Nasrallah IM, Toro C, Aguirre GK, Van Deerlin VM, Lee EB. Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau. Science. 2020 Oct 1:eaay8826. doi: 10.1126/science.aay8826. Epub ahead of print. PMID: 33004675. PubMed Icon Google Scholar Icon

Weitzman SA, Narasimhan S, He Z, Changolkar L, McBride JD, Zhang B, Schellenberg GD, Trojanowski JQ, Lee VMY. Insoluble Tau From Human FTDP-17 Cases Exhibit Unique Transmission Properties In Vivo. J Neuropathol Exp Neurol. 2020 Sep 1;79(9):941-949. doi: 10.1093/jnen/nlaa086. PMID: 32838419; PMCID: PMC7445034 PubMed Icon Google Scholar Icon

He Z, McBride JD, Xu H, Changolkar L, Kim SJ, Zhang B, Narasimhan S, Gibbons GS, Guo JL, Kozak M, Schellenberg GD, Trojanowski JQ, Lee VM. Transmission of tauopathy strains is independent of their isoform composition. Nat Commun. 2020 Jan 7;11(1):7. doi: 10.1038/s41467-019-13787-x. PubMed PMID: 3191158 PubMed Icon Google Scholar Icon

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