Cell cycle re-entry in Alzheimer's disease: a major neuropathological characteristic?

Alzheimer's disease (AD) is an irreversible, progressive brain disease that slowly destroys memory and thinking skills. With over 26 million patients in 2006, AD is the most prevalent neurodegenerative disease worldwide. Different hypotheses have been suggested to explain the pathogenesis of AD, like those involving inflammation, mitochondrial dysfunction or oxidative stress. Many of these studies have addressed amyloid plaque formation, tau hyperphosphorylation and apoptotic neuronal loss, the three main histopathological hallmarks of this disease. Increasing evidences, however, suggest another feature that can also be considered a neuropathological marker for AD: ectopic cell cycle re-entry. Cell cycle events have been frequently registered in the brains of AD patients. Although the exact starting point of cell cycle re-entry remains unclear, a number of subsequent cascades, which include events such as kinase upregulation, DNA replication and cytoskeletal alterations, have already been described. There are also increasing reports suggesting that cell cycle reactivation in mature neurons occurs as part of the apoptotic process. Upon a brief overview of the different theories and models addressing cell cycle reactivation in AD, we will describe possible mechanisms that trigger cell cycle re-entry, with special attention to links between this feature and the main neuropathological markers of AD. Finally, we will also analyze possible similarities between cell cycle dysregulation in AD and in other pathologies, such as Prion-Related Encephalopathies.