TY - JOUR
T1 - Visualization of neurofibrillary tangle maturity in Alzheimer's disease
T2 - A clinicopathologic perspective for biomarker research
AU - Moloney, Christina M.
AU - Lowe, Val J.
AU - Murray, Melissa E.
N1 - Funding Information:
This review is dedicated to the memory of the late, great Dr. Peter Davies. Without his altruism, so many of the studies cited in this manuscript may not have been possible. The investigators are supported by grants from the Alzheimer's Association (AARG-17-533458); National Institute on Aging (R01 AG054449, U01 AG57195, P30 AG062677); the Florida Department of Health, and the Ed and Ethel Moore Alzheimer's Disease Research Program (8AZ06, 20a22); and a kind gift from David and Frances Strawn. We are grateful to Virginia Phillips, Ariston Librero, Jo Landino, and Monica Castanedes-Casey for histologic support during figure development. We would like to thank Dr. Francisco García-Sierra (Cinvestav) for sharing the thiazin red image; Dr. Benjamin Wolozin (Boston University) for sharing Alz-50 antibody; Dr. Peter Davies (Northwell Health's Feinstein Institutes for Medical Research) for sharing the CP13 and PHF-1 antibody; and Dr. Nicholas Kannan (Michigan State University) for sharing tau antibodies (TauC3 originally from Dr. Lester Binder at Northwestern University and MN423 originally from Dr. Michal Novak).
Publisher Copyright:
© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association
PY - 2021/9
Y1 - 2021/9
N2 - Neurofibrillary tangles, one of the neuropathologic hallmarks of Alzheimer's disease, have a dynamic lifespan of maturity that associates with progressive neuronal dysfunction and cognitive deficits. As neurofibrillary tangles mature, the biology of the neuron undergoes extensive changes that may impact biomarker recognition and therapeutic targeting. Neurofibrillary tangle maturity encompasses three levels: pretangles, mature tangles, and ghost tangles. In this review, we detail distinct and overlapping characteristics observed in the human brain regarding morphologic changes the neuron undergoes, conversion from intracellular to extracellular space, tau immunostaining patterns, and tau isoform expression changes across the lifespan of the neurofibrillary tangle. Post-translational modifications of tau such as phosphorylation, ubiquitination, conformational events, and truncations are discussed to contextualize tau immunostaining patterns. We summarize accumulated and emerging knowledge of neurofibrillary tangle maturity, discuss the current tools used to interpret the dynamic nature in the postmortem brain, and consider implications for cognitive dysfunction and tau biomarkers.
AB - Neurofibrillary tangles, one of the neuropathologic hallmarks of Alzheimer's disease, have a dynamic lifespan of maturity that associates with progressive neuronal dysfunction and cognitive deficits. As neurofibrillary tangles mature, the biology of the neuron undergoes extensive changes that may impact biomarker recognition and therapeutic targeting. Neurofibrillary tangle maturity encompasses three levels: pretangles, mature tangles, and ghost tangles. In this review, we detail distinct and overlapping characteristics observed in the human brain regarding morphologic changes the neuron undergoes, conversion from intracellular to extracellular space, tau immunostaining patterns, and tau isoform expression changes across the lifespan of the neurofibrillary tangle. Post-translational modifications of tau such as phosphorylation, ubiquitination, conformational events, and truncations are discussed to contextualize tau immunostaining patterns. We summarize accumulated and emerging knowledge of neurofibrillary tangle maturity, discuss the current tools used to interpret the dynamic nature in the postmortem brain, and consider implications for cognitive dysfunction and tau biomarkers.
KW - Alzheimer's disease
KW - neurofibrillary tangles
KW - neuropathology
KW - tau
KW - tau positron emission tomography
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U2 - 10.1002/alz.12321
DO - 10.1002/alz.12321
M3 - Review article
C2 - 33797838
AN - SCOPUS:85103404280
SN - 1552-5260
VL - 17
SP - 1554
EP - 1574
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 9
ER -