Tau Pathology and Mechanisms

Project Overview

Neurofibrillary tangles have been shown to anatomically correlate with areas of the brain that undergo neuronal loss. To help elucidate this relationship, we have highlighted the distinct roles of both fibrillar and nonfibrillar tau in disrupting normal cognitive functions—with an emphasis on the toxicity of non-fibrillar species. By approaching this problem from multiple angles—tau kinetics, propagation rates in the brain, identifying natural isoforms, utilization of advanced biophysical methods including nonlinear optics and, most recently, cryo-EM—we quantify unique tau proteoforms. Some of our recent publications explore tau’s relationship to neuronal death and tau’s impact on neuronal firing critical for memory.

Publications

• Hyman, B (2022). “All the Tau We Cannot See.” Annual Review of Medicine 74, 503-514.
• Kumar, M. et al. (2024). “Alzheimer proteopathic tau seeds are biochemically a forme fruste of mature paired helical filaments.” Brain 147(2), 637-648.
• Zwang, T. et al. (2024). “Alzheimer disease-associated tau post-translational modification mimics impact tau propagation and uptake.” Cell Reports 43(8), 114574.