. Ectopic cell cycle events link human Alzheimer's disease and amyloid precursor protein transgenic mouse models. J Neurosci. 2006 Jan 18;26(3):775-84. PubMed.

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  1. In the last few years, Karl Herrup's group has steadfastly and beautifully expounded on the involvement of cell cycle events in Alzheimer disease pathology. Their most recent paper describing cell cycle changes in APP transgenic models further nails down this intriguing hypothesis for AD neurodegeneration.

    What is particularly exciting is the early manifestation of cell cycle events long before amyloid deposits. The presence of cell cycle events emphasizes that they are not secondary to extracellular amyloid deposition, but very early events in the AD neurodegenerative cascade. These new in-vivo findings recapitulate in-vitro findings from Rachael Neve¹s group that overexpression of FAD mutant or wild-type APP in primary neurons induces DNA synthesis (McPhie et al., 2003). They support the idea that primary defects in APP metabolism or function lead to generation of multiple AD hallmarks: ¬cell cycle activation in neurons, amyloid plaques, and microglial activation.

    Taken together with the recent paper from Peter Davies's group showing that overexpression of human tau in the absence of any endogenous mouse tau also triggers cell cycle activation in Neurons (Andorfer, 2005), it appears that both tau and APP metabolism are somehow linked to cell cycle regulation in neurons. Aberrant cell cycle activation is now emerging as a more common means of neuronal death in many in-vivo conditions.

    Available mouse models with tangles and plaques will help us pedal on towards unraveling the important links among tau, APP, and the cell cycle, and possibly identify novel ways to press the breaks on AD progression.

    References:

    . DNA synthesis and neuronal apoptosis caused by familial Alzheimer disease mutants of the amyloid precursor protein are mediated by the p21 activated kinase PAK3. J Neurosci. 2003 Jul 30;23(17):6914-27. PubMed.

    . Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J Neurosci. 2005 Jun 1;25(22):5446-54. PubMed.