-
3. Neurofibrillary Changes: The Hallmark of Alzheimer Disease
- Johns Hopkins University Press
- Chapter
- Additional Information
3 Neurofibrillary Changes The Hallmark of Alzheimer Disease Heiko Braak and Eva Braak NEUROFIBRILLARY TANGLES AND NEUROPIL THREADS A major criterion essential for postmortem diagnosis of Alzheimer disease (AD) is the presence of somatic neurofibrillary tangles (NFTs) and dendritic neuropil threads (NTs) in specific subsets of nerve cells. Individuals who have a history of cognitive decline but no NFTs or NTs are classified in the heterogeneous group of the non-Alzheimer dementias (Braak and Braak 1997). NFTs and NTs consist mainly of abnormal microtubule-associated tau protein. In healthy individuals, the main function of this protein is to stabilize microtubules, which, in addition to other functions, play an important role in transporting substances among a nerve cell’s individual compartments, which may be located at great distances from each other. Increasing aggregation of the abnormal tau protein results in impairment of this transport function and could ultimately lead to the death of the afflicted neurons. An initial turning point in the pathologic process is a marked hyperphosphorylation of the tau protein. Hydrophilic material emerges, which, at the onset, is still nonargyrophilic in nature. Cross-linkages occur in a second step. Because the resulting insoluble and argyrophilic fibrils cannot be degraded by the parent cell, they accumulate, fill large portions of the cytoplasm, extend occasionally into the proximal dendrites, and eventually crowd the nucleus into an eccentric position (Bancher et al. 1989; Iqbal et al. 1994; Goedert, Trajonowski, and Lee 1997). 54 Heiko Braak and Eva Braak FIGURE 15. Schematic drawing summarizing immunostaining with the phosphorylation-dependent anti-tau antibody AT8, compared with the corresponding Gallyas silver staining of developing neurofibrillary tangles and neuropil threads. The progression of pathological alterations of the neuronal cytoskeleton is shown from the group 1 neuron to the group 5 structure. Source: Braak et al., 1994 Recently developed antibodies that react with the abnormally phosphorylated tau protein permit a demonstration of the evolution of the cytoskeletal changes. The still-soluble and nonargyrophilic tau protein fills the perikaryon and all of the neuronal processes, a picture closely resembling the result of a successful Golgi impregnation. If that crosslinking and aggregation of the abnormal protein to insoluble and argyrophilic NFTs or NTs have not yet occurred, the neurites of such cells maintain their normal shape. Nerve cells in such a ‘‘pretangle phase’’ first appear at the typical cortical induction site of AD-related lesions (i.e., the transentorhinal region). Studying this region in brains of comparatively young individuals provides evidence of the very first changes in the cytoskeleton in the absence of beta-amyloid deposits, vascular changes, or any other overt pathologic lesions (E. Braak, H. Braak, and Mandlekow 1994, 3–23). Cells in the pretangle phase represent the earliest detectable stage in the development of lesions, when the potential for reversibility is theoretically at its highest (Figure 15). Sooner or later, however, cross-linked and argyrophilic precipitates [54.85.255.74] Project MUSE (2024-03-19 14:58 GMT) Neurofibrillary Changes: The Hallmark of Alzheimer 55 begin to appear. As the distal segments of the dendrites become twisted and dilated, they develop short appendages and probably become detached from the proximal stem (E. Braak, H. Braak, and Mandlekow 1994). Within the changed dendritic segments, the formation of slender NTs begins, and shortly thereafter a stout NFT appears in the cell body (Figure 15). The first traces of the argyrophilic abnormal material are generally associated with the intraneuronal deposits of lipofuscin or neuromelanin granules (see Alzheimer 1911, 380). The central portions of larger NFTs form a dense feltwork around the pigment granules. It is possible that these granules provide initiation sites supporting oxidative cross-linking reactions. In any event, other neuronal inclusions, such as Lewy bodies, Hirano bodies, or granulovacuolar bodies, have no close association with the initial NFTs. After the final deterioration of the parent cell, the NFT material remains visible in the tissue for years as an extraneuronal ‘‘ghost’’ or ‘‘tombstone’’ tangle, marking the site at which the neuron was destroyed. In the course of this transformation, the NFT gradually becomes less densely twisted and loses much of its argyrophilia . Finally, even the extraneuronal NFT remnants completely disappear (Simchowicz 1911; Grünthal 1930; von Braunmühl 1957; Probst, Langui, and Ulrich 1991; Braak and Braak 1994). DEPOSITS OF BETA-AMYLOID AND NEURITIC PLAQUES Accompanying changes that generally develop later in the course of the disease include extracellular depositions of beta-amyloid protein and the formation of neuritic plaques (NPs...