Cell cycle regulatory failure in neurones: causes and consequences

The number of Alzheimer's disease sufferers shows an alarming increase throughout the world. Therefore elucidation of the pathogenic mechanisms leading to Alzheimer's disease and the design of effective treatment, preventive or curative, became imperative. In the last few years several groups have found evidence indicating that the development of Alzheimer-type pathology and the associated excess cell death is the consequence of an aberrant re-entry of neurones into the cell division cycle. We believe that neuronal cell cycle re-entry is followed by regulatory failure that allows neurones to progress into the late stages of the cycle. At this stage, in apoptosis incompetent neurones, the active kinases lead to tau hyperphosphorylation, and the amyloid precursor protein is processed into amyloidogenic fragments. Thus the cell cycle arrest will lead to either the development of Alzheimer's type pathology or to apoptotic neuronal death. Although there are several studies aimed at the elucidation of the precise pathways and mechanisms by which the cell cycle disturbances may lead to Alzheimer's disease there is precious little known about the possible causes of the neuronal cell cycle re-entry. On the other hand we can only speculate on the mechanisms that lead to the subsequent regulatory failure. (C) 2000 Elsevier Science Inc. All rights reserved.