(Click on picture for larger view)
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1. H&E-stained tangle |
2. Tangle stained with H&E (left) and silver (right) |
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Neurofibrillary tangles were first described by Alois Alzheimer in one of his patient's suffering from the disorder now referred to as Alzheimer's disease.
Neurofibrillary tangles are an intracellular abnormality, involving the cytoplasm of nerve cells. Although neurofibrillary tangles can be seen in microscopic sections stained with hematoxylin and eosin (H&E; Figure 1), they are most readily visualized in sections stained by using silver impregnation techniques (e.g., Bielschowsky stain or the Bodian stain; Figure 2). Neurofibrillary tangles can also be stained with Congo red or with the fluorescent dye thioflavine-S (Figure 3).
(Click on picture for larger view)
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1. H&E-stained tangle |
2. Tangle stained with H&E (left) and silver (right) |
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3. Apple green birefringence of Congo red-stained tangle |
In Alzheimer's disease, neurofibrillary tangles are generally found in the neurons of the cerebral cortex and are most common in the temporal lobe structures, such as the hippocampus and amygdala. Neurofibrillary tangles can be extremely numerous when viewed at low-power (Figures 4 and 5).
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4. Numerous tangles (example at arrow) in hippocampus |
5. Numerous tangles in amygdala |
Neurofibrillary tangles in pyramidal neurons of the cerebral cortex often have a flame-shape appearance, filling the neuronal cell body and apical dendrite (Figure 6). In other neurons, neurofibrillary tangles often have a more spherical (globose or globoid) appearance. In the neuropil of the cerebral cortex, short, sometimes curly, threadlike structures (termed neuropil threads or dystrophic neurites) represent neuronal dendrites or axons containing the neurofibrillary tangles.
Ultrastructural visualization of the neurofibrillary tangles using electron microscopy (EM) has shown them to consist of paired 10 nanometer diameter filaments twisted around one another in a helical fashion ("paired helical filaments"; Figure 7).
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6. Silver-stained tangle in cerebral cortex |
7. Paired helical filaments visualized by using EM |
Biochemical analysis has shown that the neurofibrillary tangles are composed mainly of abnormally-phosphorylated tau protein ( a neuron-specific phosphoprotein that is the major constituent of neuronal microtubules). Variable amounts of other proteins can also be found attached to the abnormally-phosphorylated tau protein of the neurofibrillary tangles.
Note that neurofibrillary tangles are not unique to Alzheimer's disease, but can be found in a variety of other neurologic disorders: in substantia nigra neurons in postencephalitic Parkinsonism, throughout the nervous system in the Parkinsonism-dementia-ALS complex disorder of the Chamorro population on Guam, in the cerebral cortex in dementia pugilistica (“punch-drunk syndrome”), and in the brain stem and thalamus in Steele-Richardson-Olszewski progressive supranuclear palsy (PSP).