Activation of c-Jun N-terminal kinase and p38 in an Alzheimer's disease model is associated with amyloid deposition.
The mechanisms by which neurons and synapses are lost in Alzheimer's disease (AD) are not completely understood. To characterize potential signaling events linked to AD pathogenesis, activation-specific antibodies were used to examine mitogen-activated protein kinase (MAPK) kinase pathways at various ages in mice transgenic for human amyloid precursor protein-695 with the Swedish familial AD mutations (Tg2576) and homozygous for a P264L familial AD mutation introduced by targeting of the presenilin-1 gene (PS1(P264L)). Although the c-Jun N-terminal kinase (JNK) and p38 pathways were significantly activated in the cortex at both 7 and 12 months of age, there was no significant activation of the extracellular signal-regulated kinase pathway. MAPK kinase-4, an upstream activator of JNK, was also significantly activated at 7 and 12 months, whereas c-Jun, a downstream effector of JNK-associated apoptotic signaling, was not induced. The lack of c-Jun activation is consistent with the absence of neuronal loss in both cortex and hippocampal CA1 at 12 months. The JNK activation was localized to amyloid deposits, within neurites containing phosphorylated tau. Synaptophysin was quantified biochemically as a measure of synaptic integrity and was significantly reduced in an age-dependent manner in the Tg2576/PS1(P264L) cortex but not in either PS1(P264L) or Tg2576 cortex. Stress-responsive MAP kinase pathways were activated in the brain of the Tg2576/PS1(P264L) AD model, and this activation was coincident with the age-dependent increase in amyloid deposition, tau phosphorylation, and loss of synaptophysin.
Savage
Mary J
MJ
Department of Neurobiology, Cephalon Inc., West Chester, Pennsylvania 19380, USA. msavage@cephalon.com
Lin
Yin-Guo
YG
Ciallella
John R
JR
Flood
Dorothy G
DG
Scott
Richard W
RW
D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019943:Amino Acid Substitution; D000682:Amyloid / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D002452:Cell Count; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004789:Enzyme Activation; D018390:Gene Targeting; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016501:Neurites / Q000201:enzymology / Q000473:pathology; D009474:Neurons / Q000473:pathology; D010766:Phosphorylation; D053764:Presenilin-1; D015398:Signal Transduction; D016708:Synaptophysin / Q000172:deficiency / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases; D016875:tau Proteins / Q000378:metabolism
D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D016708:Synaptophysin; D016875:tau Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases