Thomas Wisniewski, MD - Neurologist
Primary tabs
JAD profile
Affiliation(s):
New York University School of Medicine
ORCID URL:
Areas of Interest:
Alzheimer's disease
Biography & Research:
Dr. Thomas Wisniewski is a translational neuroscientist/physician whose work over many years has been novel and innovative. His work is highly cited, with an h-index of ~70 and >18,000 citations. His work has also lead to 22 issued US patents, related to novel diagnostic and therapeutic approaches for AD. The various therapeutic approaches he has been developing have come to fruition in the last few years, resulting in a number of recent important scientific findings; in particular, related to immunotherapeutic approaches for both prion and Alzheimer’s diseases (AD), as well as developing novel proteomic approaches to better understand the pathogenesis of neurodegenerative disorders. He has made significant contributions, delineating the role of apolipoprotein (apo) E in AD and developing a therapeutic approach based on the Aβ/apoE interaction. Dr. Wisniewski was the first to show the potential effectiveness of both active and passive immunization approaches for prion infection using mouse adapted scrapie strains in wild type animals. He has shown that this approach is partially effective in preventing chronic wasting disease (CWD) in white tailed deer. This is the first time a vaccination approach has been tried in a wild-type population which is susceptible to a naturally occurring prion disease and shown to be at least partially effective. Recently, as a result of his concurrent work on AD and prion pathogenesis, he has made the discovery that PrPC expression regulates the emergence of AD related pathology (tau pathology) following traumatic brain injury.
Dr. Wisniewski early work on AD vaccination influenced the field to be wary of potential toxicity when using active immunization with the native Aβ peptides. Dr. Wisniewski’s group has developed immunomodulation to ameliorate both amyloid β and tau related pathology concurrently. This approach induces an immune response specific to the shared pathological conformation of both oligomer/fibrillar Aβ and tau, as well as other amyloid proteins, with a number of recent publications on this approach. This is a ground breaking concept since such an approach could allow for the simultaneous targeting of multiple amyloid prone pathological proteins and has the potential to treat multiple neurodegenerative diseases.
Dr. Wisniewski has also promoted the hypothesis that senescence of microglia/ macrophage function plays an important role in AD pathogenesis. His group was the first to show that stimulation of innate immunity via the Toll-like 9 receptor (TLR9) with cytosine-guanosine (CpG) containing DNA oligodeoxynucleotides (ODNs) is an effective way to ameliorate AD pathology. He has recently shown that this methodology is effective against all three core lesions in AD: amyloid plaques, congophilic angiopathy and tau related pathology, without apparent toxicity. This opens a novel immunomodulatory approach that can be used alone or in combination with other methods to ameliorate both plaque and tau related pathology, as recently reviewed in the J. Neuroscience. He is currently evaluating this approach in non-human primates (NHP, squirrel monkeys), as in his work he has cautioned against the premature translation of therapeutic success in transgenic mouse models of AD to clinical trials. The on-going work in NHPs has very promising preliminary results. Since the use of CpG ODN has been shown to be safe in humans in other settings (cancer, vaccines etc.), if the extensive mouse data can be reproduced in the NHP, this approach can likely be effectively translated to humans.
Dr. Wisniewski has also made significant contributions to the study of the role of apoE in AD. He had proposed a key role for apolipoprotein E in driving amyloid β accumulation in late-onset AD. He coined the term “pathological chaperone” to denote the role of apoE in AD, prior to the discovery of linkage of apoE4 to late-onset AD. Using this hypothesis Dr. Wisniewski’s group has developed a novel therapeutic approach to treat AD-related pathology by blocking the binding of Aß and apoE. This approach has been shown recently to be highly effective in multiple AD transgenic lines, reducing the amyloid plaque burden, Aβ40/42 peptide brain levels, oligomer levels and tau pathology, with resulting cognitive benefits. He recently developed peptoid candidates that inhibit the Aß/apoE interaction, which have the potential to be progressed to clinical testing.
Recently his laboratory has developed an unbiased localized proteomic strategy that produces robust data utilizing archival formalin, fixed paraffin embedded tissue. He used this method to perform the most extensive analysis of amyloid plaques, as well as to characterize the amyloid proteome of a distinct subtype of AD: rapidly progressive AD.
