Pin1 in Alzheimer's disease: multiple substrates, one regulatory mechanism?
Presence of neuritic plaques and neurofibrillary tangles in the brain are two neuropathological hallmarks of Alzheimer's disease (AD), although the molecular basis of their coexistence remains elusive. The neurofibrillary tangles are composed of microtubule binding protein Tau, whereas neuritic plaques consist of amyloid-beta peptides derived from amyloid precursor protein (APP). Recently, the peptidyl-prolyl cis/trans isomerase Pin1 has been identified to regulate the function of certain proteins after phosphorylation and to play an important role in cell cycle regulation and cancer development. New data indicate that Pin1 also regulates the function and processing of Tau and APP, respectively, and is important for protecting against age-dependent neurodegeneration. Furthermore, Pin1 is the only gene known so far that, when deleted in mice, can cause both Tau and Abeta-related pathologies in an age-dependent manner, resembling many aspects of human Alzheimer's disease. Moreover, in the human AD brain Pin1 is downregulated or inhibited by oxidative modifications and/or genetic changes. These results suggest that Pin1 deregulation may provide a link between formation of tangles and plaques in AD.
Balastik
Martin
M
Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 77 Ave. Louis Pasteur, Boston, MA 02115, USA.
Lim
Jormay
J
Pastorino
Lucia
L
Lu
Kun Ping
KP
D000544:Alzheimer Disease / Q000201:enzymology*; D001921:Brain / Q000201:enzymology; D006801:Humans; D008959:Models, Neurological; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009474:Neurons / Q000201:enzymology; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D012016:Reference Values; D024801:Tauopathies / Q000201:enzymology
D000072340:NIMA-Interacting Peptidylprolyl Isomerase; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse