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Neurofibrillary tangles

Neurofibrillary tangles are comprised of bundles of filaments twisted about each other in pairs (paired helical filaments or PHF). PHF are composed of a protein called tau, which is a normal protein present in all nerve cells and functions to stablise normal fibrous structures known as microtubules.

NFTs are intraneuronal lesions composed primarily (95%) of PHFs, but also straight filaments (SFs). PHFs have a periodicity of 80nm and a diameter of 8-20nm, while SFs lack periodicity and have a diameter of 15nm (Spillantini and Goedert 1998 PHF morphology varies with intracellular location and in addition to the NFT, they are components of the plaque-free neuropil threads (NTs) and the dystrophic neurites of neuritic plaques (NPs) (Kurt et al 1997 Both PHFs and SFs are composed of the microtubule-associated protein tau (Kosik et al 1986 Crowther 1991 Within PHFs and SFs tau is abnormally and hyper phosphorylated.

Only a few neuronal types are prone to develop NFTs and NTs. In the cerebral cortex, all NFT-bearing nerve cells belong to the class of pyramidal neurons, and in subcortical nuclei the most vulnerable cells have a conspicuously lengthy axon (reviewed by Braak et al 1999 The specific hierarchical pattern of NFT development closely matches the pattern of neuronal plasticity in the adult brain, and the regions most early and severely affected are involved in learning and memory processes that require continuous refitting of connectivity throughout life (reviewed by Arendt 2004 The consistent development of tangle pathology allows classification of six stages (Braak I-VI), dependent on the brain regions affected.

Stages I and II usually affect only the pre-α layer of the transentorhinal region and patients with pathologies in these regions do not show cognitive impairment. At stages III and IV, there are a greater number of (NFTs) and (NTs) in the limbic system. In stage III the pre-α layer of the entorhinal and transentorhinal regions are destroyed and mild changes are observed in the hippocampus. Stage IV includes changes in the pri-α layer. Many patients whose brains showed pathologies consistent with stages III and IV exhibit an impairment of cognition, however, the pathological changes do not meet the criteria for definite diagnosis of AD as the majority of the neocortex is not affected, there is minor destruction of the cerebral cortex and there is no detectable macroscopic atrophy. Stages V and VI of the Braak classification corresponds to CERAD criteria for the neuropathological confirmation of clinical diagnosis of AD. Brains in these final stages have large numbers of NFTs and NTs in virtually all subdivisions of the cerebral cortex and neocortical association areas are particularly severely destroyed.

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Neurofibrillary tangles