The role of neurofibrillary tangles in Alzheimer disease

The neuropathological diagnosis of Alzheimer disease relies on the presence of both neurofibrillary tangles and senile plaques. The number of neurofibrillary tangles is tightly linked to the degree of dementia, suggesting that the formation of neurofibrillary tangles more directly correlates with neuronal dysfunction. The regional pattern of areas affected by neurofibrilllary tangle formation during the course of the disease is relatively stereotyped. Neurofibrillary tangles are composed of highly phosphorylated forms of the microtubule-associated protein tau. Phosphorylated tau proteins accumulate early in neurones, even before formation of neurofibrilllary tangles, suggesting that an imbalance between the activities of protein kinases and phosphatases acting on tau is an early phenomenom. The latter might be related to changes in signalling through transduction cascades, since many of the protein kinases generating phosphorylated tau species participate in signalling pathways. The accumulation of neurofibrilllary tangles and phosphorylated tau species is associated with disturbances of the microtubule network, and, as a consequence of the latter of axoplasmic flows. The mechanistic relationship between the formation of neurofibrilllary tangles and senile plaques is still poorly understood and in vivo formation of neurofibrilllary tangles in experimental models has not yet been achieved. Future animal models, e.g. transgenic animals expressing combined key human proteins, will hopefully faithfully reproduce all the major cellular lesions of the disease.