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Defective brain microtubule assembly in Alzheimer's disease
Abstract:
Brains obtained within 2-4 hours post mortem and histopathologically confirmed for Alzheimer's disease and non-Alzheimer brains from age-matched controls were examined for in-vitro assembly of microtubules and neurofilaments. Microtubule assembly was observed only in control but not in Alzheimer brains, and neurofilaments were obtained from both types of brain. The microtubule-associated protein tau, which stimulates assembly of microtubules from tubulin, was abnormally phosphorylated in Alzheimer but not in control brain microtubule preparations. Alzheimer brains did not show the presence of any inhibitor of microtubule assembly or any abnormality of tubulin. DEAE-dextran, a polycation which mimics tau in stimulating microtubule assembly, induced the assembly of microtubules in Alzheimer brain. Tubulin from both normal and Alzheimer brains was labelled on western blots by a monoclonal antibody to the tyrosinylated carboxy-terminal epitope of alpha tubulin. These studies suggest that in Alzheimer's disease tubulin can be assembled into brain microtubules, but the process is defective, probably because of abnormal phosphorylation of tau. This post-translational alteration of tau might be the cause of the neurofibrillary abnormality in Alzheimer's disease.
Insights
Alzheimer
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Alzheimer's disease is characterized by neurofibrillary tangles.
- Microtubules are essential for neuronal structure and function.
- The role of tau protein in microtubule assembly in Alzheimer's disease is not fully understood.
Purpose of the Study:
- To investigate the in-vitro assembly of microtubules and neurofilaments in Alzheimer's disease brains.
- To determine the role of tau protein phosphorylation in microtubule assembly defects in Alzheimer's disease.
Main Methods:
- Post-mortem brain tissue analysis (Alzheimer's and control).
- In-vitro microtubule and neurofilament assembly assays.
- Western blot analysis using antibodies against tubulin and phosphorylated tau.
Main Results:
- Microtubule assembly was impaired in Alzheimer's brains but not in controls.
- Abnormal phosphorylation of tau protein was observed in Alzheimer's brains.
- Tubulin from Alzheimer's brains could be assembled into microtubules when stimulated by DEAE-dextran, indicating tubulin integrity.
Conclusions:
- Tubulin can assemble into microtubules in Alzheimer's disease brains, but the process is defective.
- Abnormal tau phosphorylation is likely responsible for the defective microtubule assembly in Alzheimer's disease.
- Post-translational modification of tau may cause neurofibrillary abnormalities in Alzheimer's disease.