Hyperactivation of signal transduction systems in Alzheimer's disease.

Abstract

A compromise or deregulation in signal transduction cascades could adversely affect cellular functions and possibly contribute to cell death. In recent years, it has become increasingly apparent that pronounced activation of neuronal signal transduction systems is a characteristic of AD brain. There is evidence that signal transduction systems play a role in the formation or development of these pathological features of AD. Aberrant activity and localization of components of signaling mechanisms (growth factors, their receptors, protein kinases, phosphoprotein phosphatases, and phosphoproteins) are closely associated with the intracellular accumulation of PHF, the extracellular deposition of amyloid, and the formation of neuritic plaques in AD brain. In particular, immunohistochemical studies reveal increased levels of neuronal staining for APP, possibly an important growth factor in AD, both in frontal cortex and hippocampus. Anti-APP immunostaining is also associated with the neuritic component of plaques. Additionally, PKC(beta II) immunostaining is increased in the neuronal cell body and neuropil of AD samples, particularly in association with plaques, suggesting a postsynaptic involvement of this enzyme. On the other hand, PKC(beta I) immunostaining is associated with axonal staining particularly in the sprouting neurites of plaques. Sprouting neuritic components of plaques are immunopositive with other growth-associated proteins, such as GAP43, MARCKS, and spectrin. Immunoreactivity of other members of signal transduction systems such as Fos and stathmin are all increased in AD hippocampal neurons. On the other hand, several protein kinases and phosphoproteins were immunolocalized to tangles. Thus, the hyperactivation and dysfunction of signal transduction systems could be involved in the pathogenesis of AD.