Selective induction of calcineurin activity and signaling by oligomeric amyloid beta.
Alzheimer's disease (AD) is a terminal age-associated dementia characterized by early synaptic dysfunction and late neurodegeneration. Although the presence of plaques of fibrillar aggregates of the amyloid beta peptide (Abeta) is a signature of AD, evidence suggests that the preplaque small oligomeric Abeta promotes both synaptic dysfunction and neuronal death. We found that young Tg2576 transgenic mice, which accumulate Abeta and develop cognitive impairments prior to plaque deposition, have high central nervous system (CNS) activity of calcineurin (CaN), a phosphatase involved in negative regulation of memory function via inactivation of the transcription factor cAMP responsive element binding proteins (CREB), and display CaN-dependent memory deficits. These results thus suggested the involvement of prefibrillary forms of Abeta. To investigate this issue, we compared the effect of monomeric, oligomeric, and fibrillar Abeta on CaN activity, CaN-dependent pCREB and phosphorylated Bcl-2 Associated death Protein (pBAD) levels, and cell death in SY5Y cells and in rat brain slices, and determined the role of CaN on CREB phosphorylation in the CNS of Tg2576 mice. Our results show that oligomeric Abeta specifically induces CaN activity and promotes CaN-dependent CREB and Bcl-2 Asociated death Protein (BAD) dephosphorylation and cell death. Furthermore, Tg2576 mice display Abeta oligomers and reduced pCREB in the CNS, which is normalized by CaN inhibition. These findings suggest a role for CaN in mediating effects of oligomeric Abeta on neural cells. Because elevated CaN levels have been reported in the CNS of cognitively impaired aged rodents, our results further suggest that abnormal CaN hyperactivity may be a common event exacerbating the cognitive and neurodegenerative impact of oligomeric Abeta in the aging CNS.
Reese
Lindsay C
LC
Department of Neuroscience and Cell Biology, University of Texas Medical Branch at Galveston, Texas, USA.
Zhang
WenRu
W
Dineley
Kelly T
KT
Kayed
Rakez
R
Taglialatela
Giulio
G
D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000502:physiology*; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D019703:Calcineurin / Q000096:biosynthesis* / Q000502:physiology; D065095:Calcineurin Inhibitors; D045744:Cell Line, Tumor; D002490:Central Nervous System / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000737:chemistry / Q000502:physiology; D058255:Protease Nexins; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D065095:Calcineurin Inhibitors; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D019703:Calcineurin
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