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Self-assembly of the brain MAP-2 microtubule-binding region into polymeric structures resembling Alzheimer filaments
E Y Zhang1, M A DeTure, M R Bubb
1Department of Biochemistry & Molecular Biology, College of Medicine, University of Florida, Gainesville 32610-0245, USA.
Abstract:
The neuronal microtubule-associated protein known as MAP-2 has not been considered to be a subunit of paired helical filaments (PHFs) in neurofibrillary tangles seen in Alzheimer's Disease. We now describe the assembly of paired helical filament-like structures from MAP-2's 203-residue microtubule-binding region (MTBR). SDS gel electrophoresis and equilibrium ultracentrifugation suggest that a dimeric form, cross-linked by an interchain disulfide, is involved in polymerization. MAP-2 MTBR polymers bind thioflavin-S, a dye used to histochemically localize Alzheimer neurofibrillary tangles. Our finding that PHF-like structures assemble from a MAP-2 fragment raises new questions about MAP-2's role in the etiology of Alzheimer's Disease.
Insights
Microtubule-associated protein 2 (MAP-2) fragments can assemble into paired helical filament-like structures. These structures bind Thioflavin-S, suggesting a novel role for MAP-2 in Alzheimer's Disease pathology.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau are hallmarks of Alzheimer's Disease (AD).
- Neuronal microtubule-associated protein 2 (MAP-2) has not been previously implicated as a component of paired helical filaments (PHFs) in AD.
Purpose of the Study:
- To investigate the potential of MAP-2 to form paired helical filament-like structures.
- To explore the role of MAP-2 in the etiology of Alzheimer's Disease.
Main Methods:
- Assembly of paired helical filament-like structures from the microtubule-binding region (MTBR) of MAP-2.
- SDS gel electrophoresis and equilibrium ultracentrifugation to analyze polymerization.
- Thioflavin-S binding assays to assess filament properties.
Main Results:
- MAP-2's 203-residue MTBR self-assembled into PHF-like structures.
- Evidence suggests a disulfide-crosslinked dimeric form of MAP-2 MTBR is involved in polymerization.
- The assembled MAP-2 MTBR polymers demonstrated binding affinity for Thioflavin-S.
Conclusions:
- MAP-2 MTBR can form structures resembling those found in Alzheimer's neurofibrillary tangles.
- This finding suggests a potential, previously unrecognized role for MAP-2 in Alzheimer's Disease pathogenesis.
- Further research is warranted to elucidate MAP-2's specific contribution to AD.