Final answer:
Tau detaches from microtubules when it becomes hyper-phosphorylated, leading to microtubule disassembly and the formation of neurofibrillary tangles.
Step-by-step explanation:
Tau falls off microtubules when it becomes hyper-phosphorylated, leading to a change in its conformation. In neurons, tau protein normally binds to and stabilizes microtubules. However, with hyper-phosphorylation, tau loses its ability to support the microtubule structure, resulting in microtubule disassembly and the formation of neurofibrillary tangles. These tangles clump together, and as evidenced by immunostaining, they are associated with neurodegenerative diseases like Alzheimer's, where they can be observed in brain regions such as the hippocampus.