Synaptic plasticity and cell cycle activation in neurons are alternative effector pathways: the 'Dr. Jekyll and Mr. Hyde concept' of Alzheimer's disease or the yin and yang of neuroplasticity

Abstract

Mental actions are based on the dynamic organization of neuronal networks. In particular, phylogenetically young brain areas (e.g., cortical associative circuits) involved in the realization of higher brain functions are continuously re-adjusted to meet environmental demands. The mechanisms of synaptic plasticity, i.e., of structural stabilization and labilization underlying a life-long synaptic remodelling, are largely based on external morphoregulatory cues and internal signalling pathways that non-neuronal cells have phylogenetically acquired to sense their relationship to the local neighbourhood and to control after development is completed proliferation and differentiation in the process of tissue repair and regeneration. After having withdrawn from the cell cycle, differentiated neurons are, thus, able to use molecular mechanisms primarily developed to control proliferation alternatively to control synaptic plasticity. The existence of these alternative effector pathways within a neuron puts it at risk to erroneously convert signals derived from plastic synaptic changes into positional cues that will activate the cell cycle. This cell cycle activation potentially links synaptic plasticity to cell death. Preventing cell cycle activation by locking neurons in a differentiated but still highly plastic phenotype will, thus, be crucial to prevent neurodegeneration.

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

“…Further, Pin1 was also identified by redox proteomics as oxidatively modified protein in AD hippocampus (65,363). Oxidation and decreased levels and activity of this protein could favor the formation of NFTs, SP, and subsequent synapse or cell loss due to cell arrest (20). Decreased activity of Pin1 is consistent with increased phosphorylation of Tau protein, which could destabilize the microtubule assembly (59,116), eventually leading to disruption of the axonal cytoskeleton.…”

Deregulated Cdk5 Triggers Aberrant Activation of Cell Cycle Kinases and Phosphatases Inducing Neuronal Death

“…Early loss of neurons in the entorhinal cortex is preceded by the appearance of a large numbers of cell cycle markers (Yang et al, 2003). Only degenerating neurons are positive for different cell cycle proteins, suggesting that cell cycle antigens may be the best markers for dying neurons in all cell stages (Yang et al, 2003;Arendt et al, 2003). Additional evidence for the link between cell cycle and AD is the presence of higher levels of active cell cycle proteins in the hippocampus, the region most vulnerable in AD pathology.…”

The Role of Smad Proteins for Development, Differentiation and Dedifferentiation of Neurons

“…Typical clinical symptoms are memory loss, disturbed activities of daily life and deficiency of social competence. Common morphological correlates to the clinical features are extracellular βA4-plaque depositions, intraneuronal tau pathology, neuronal cell death, and cell cycle activation [189].…”