Aberrancies in signal transduction and cell cycle related events in Alzheimer's disease

Neurodegeneration in Alzheimer's disease (AD) is associated with the appear ance of dystrophic neuronal growth profiles that most likely reflects an ab errant attempt of neuronal repair. This process of neuronal reorganisation, which eventually goes awry and becomes a disease itself, might be intitiat ed physiologically as a response to neuronal injuries. Minor neuronal. dama ge due to a variety of life events or genetic pertubations that are usually compensated in the normal adult brain by adaptation and repair might thus be amplified and accumulated, thereby resulting in a progressive neurodegen eration. The present paper summarizes recent evidence supporting the hypoth esis that a primary impairment of intracellular signal transduction that is mediated by a hierarchy of phosphorylation signals and associated with a a borted attempt of neurons to re-enter the cell-cycle is a key element in th e pathomechanism of AD. These changes might result in malfunction of neuron al adaptation and repair and eventually lead to neuronal death. During the process of aging as well as in chronic neurodegenerative disorde rs such as Alzheimer's disease (AD), the continuous but rather slow action of pathogenetic factors might give room for the activation of compensatory mechanisms, serving to regain a neuronal population much of its synaptic co nnectivity in the presence of cell loss. An upregulation in the capacity to synthesize and store neurotransmitters (Lapchak et al., 1991), an increase d expression of trophic factors (Hellweg et al., 1990; Arendt et al., 1995a ,b), as well as regenerative sprouting (Fritschy and Grzanna, 1992), synapt ic enlargement (Scheff et al., 1990; Lippa et al., 1992), and neosynaptogen esis (Ramirez and Ulfhake, 1992) have been described among other processes.