Aberrant protein phosphorylation and cytoarchitecture in Alzheimer's disease.

The neurofibrillary tangle (NFT) is a pathological cytoskeletal structure found in diseased neurons of patients with Alzheimer's disease (AD). Immunocytochemical studies have revealed that the NFT contains cytoskeletal components which are excessively phosphorylated. It is not known if the overphosphorylation of cytoskeletal components is causally involved in the formation of NFT or if it is a simple reflection of abnormal cytoskeletal structure. A major pathological feature of AD is selective neuronal degeneration. Because neuronal survival is supported by the combined function of many growth factors which trigger various protein kinase reactions, some of the cascade reactions necessary for the survival of neurons may be aberrant in AD neurons. In fact, the concentration of Ca2+/phospholipid-dependent protein kinase (protein kinase C, PK-C) is lower in AD cortex than in control cortex. Furthermore, the endogenous phosphorylation reaction catalyzed by this kinase revealed diminished levels of phosphate incorporation into a major PK-C substrate, Mr 86,000 protein (P86). Is this aberrant PK-C system pertinent to NFT formation? The number of tangles does not correlate well with the degree of PK-C abnormality. Therefore, some other protein kinases may be involved in NFT formation. Under conditions where cAMP-dependent protein kinase (PK-A) and PK-C were not stimulated, the levels of in vitro phosphorylation of a Mr 60,000 protein (P60) by an endogenous kinase were found to be increased in AD cortex as compared to control. This increased P60 phosphorylation was not detected in AD patients without NFT, suggesting the involvement of P60 phosphorylation in the process of tangle formation. In fact, the degree of the P60 phosphorylation showed a positive correlation with tangle numbers. P60 phosphorylation was induced in neurons under various conditions where PK-C activity was impaired. Thus, it is possible that the aberrant P60 phosphorylation is consequential to aberrant PK-C. The other protein kinase relevant to NFT formation is casein kinase II (CK-II). CK-II concentration is reduced in AD cortex but its specific activity is increased. Immunohistochemical study of CK-II revealed a general decrease in its staining in AD neurons and a strong staining of NFT. Conversely, anti-paired helical filament antibody cross-reacted with partially purified CK-II. Thus, many protein kinases are affected in AD and some of them are associated with aberrant cytoarchitecture in AD neurons. Further study of protein phosphorylation in AD neurons should prove useful in elucidating the formation of pathological cytoarchitecture and eventual cell death in this disease.