Prof. Thomas Wisniewski

Here the authors show that the binding of amyloid-β (Aβ) oligomers to cellular prion protein (PrPc) activates Fyn kinase. Aβ stimulation of PrPc/Fyn signaling drives phosphorylation of the NR2B subunit of NMDA receptors, with a subsequent loss of receptor surface expression and dendritic spines. Amyloid-beta (Aβ) oligomers are thought to trigger Alzheimer's disease pathophysiology. Cellular prion protein (PrPC) selectively binds oligomeric Aβ and can mediate Alzheimer's disease–related phenotypes. We examined the specificity, distribution and signaling of Aβ-PrPC complexes, seeking to understand how they might alter the function of NMDA receptors (NMDARs) in neurons. PrPC is enriched in postsynaptic densities, and Aβ-PrPC interaction leads to Fyn kinase activation. Soluble Aβ assemblies derived from the brains of individuals with Alzheimer's disease interacted with PrPC to activate Fyn. Aβ engagement of PrPC-Fyn signaling yielded phosphorylation of the NR2B subunit of NMDARs, which was coupled to an initial increase and then a loss of surface NMDARs. Aβ-induced dendritic spine loss and lactate dehydrogenase release required both PrPC and Fyn, and human familial Alzheimer's disease transgene–induced convulsive seizures did not occur in mice lacking PrPC. These results delineate an Aβ oligomer signal transduction pathway that requires PrPC and Fyn to alter synaptic function, with deleterious consequences in Alzheimer's disease.

1 February 1992 in Neuroscience Letters

Journal Article

Apolipoprotein E: A pathological chaperone protein in patients with cerebral and systemic amyloid

Thomas Wisniewski

Blas Frangione

Many biochemically diverse proteins can give rise to amyloid fibrils; however, they are all accompanied by P component and glucosaminoglycans. With antibodies specific to apolipoprotein E (apo E) we used immunohistochemical techniques to test for the presence of this protein in both cerebral and systemic amyloid. We found apo E immunoreactivity in all tested types of cerebral and systemic amyloid. In amyloid deposits apo E P, component and glucosaminoglycans may be acting as 'pathological molecular chaperones'. The latter we define as a group of unrelated proteins that induce beta-pleated conformation in amyloidogenic polypeptides.

About Me

Thomas Wisniewski, M.D., is board certified Neurologist and Neuropathologist. He is Professor of Neurology, Pathology and Psychiatry. Dr. Wisniewski serves as the Director of the NYU NIH funded Alzheimer’s Disease Center and is Director of the Conformational Disorders Laboratory, the Center of Cognitive Neurology, the Pearl Barlow Memory Disorders Center, the Division of Aging and Dementia and the Neuropathology Fellowship program. For over 30 years. He has been working on elucidating the pathogenesis of Alzheimer's disease (AD), Down Syndrome (DS) and prion diseases, with an aim to develop possible therapeutic strategies. This work has led to over 400 peer reviewed publications, 30 issued patents and has been continuously funded by NIH for >25yrs. He is the field chief editor of the journal Frontiers in Aging Neuroscience. His work has helped develop novel therapeutic methods for AD, such as modulating the interactions between apolipoprotein E and amyloid β as well as various immunotherapeutic approaches that affect both the adaptive and innate immune systems. Recently, he has developed an unbiased proteomic methodology that produces robust data utilizing archival formalin, fixed paraffin embedded human tissue and used this method perform the most extensive proteomic analysis of amyloid plaques and phosphorylated tau, as well as to characterize the amyloid proteome of a distinct subtypes of AD: rapidly progressive AD, early onset AD and AD in Down syndrome.

Prof. Thomas Wisniewski

Prof. Thomas Wisniewski

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