APP knockout attenuates microglial activation and enhances neuron survival in substantia nigra compacta after axotomy.
Focal microglial activation and progressive dopaminergic neurodegeneration in substantia nigra compacta (SNc) have characterized Parkinson's disease (PD). We have hypothesized that the microglial response may be provoked by molecular signals from chronically stressed SNc neurons. To test whether amyloid precursor protein (APP) could serve as such a signal, we evaluated microglial activation in SN after unilateral transection of the medial forebrain bundle (MFB) in mice either wild-type (WT) or null (KO) for APP. WT and KO mice displayed comparable microglial response at the MFB transection site. In WT mice microglial activation was first apparent in the ipsilateral SN at 3 days postlesion (dpl), marked by morphological change and increased isolectin immunoreactivity. The microglial response intensified at 7 dpl and persisted in the medial nigra through 14 dpl. In contrast, in KO mice activated microglia appeared predominantly at 7 dpl, with little activation at 3 dpl and none at 14 dpl. Neuron number in affected WT SNc at 14 dpl was significantly reduced compared with loss in affected KO SNc. The delayed and limited local microglial activation and increased neuron survival in response to distal axotomy of SNc neurons in APP KO mice are consistent with the important role APP in neuronal stress responses in vivo.
DeGiorgio
Lorraine A
LA
Burke Medical Research Institute, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, White Plains, New York 10605, USA. ldegiorg@burke.org
Shimizu
Yoshinori
Y
Chun
Hong S
HS
Cho
Byung-Pil
BP
Sugama
Shuei
S
Joh
Tong H
TH
Volpe
Bruce T
BT
D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D019771:Axotomy; D002470:Cell Survival / Q000502:physiology; D004298:Dopamine / Q000502:physiology; D008474:Medial Forebrain Bundle / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000502:physiology*; D009474:Neurons / Q000166:cytology*; D015398:Signal Transduction / Q000502:physiology; D013378:Substantia Nigra / Q000166:cytology* / Q000502:physiology*
D016564:Amyloid beta-Protein Precursor; D004298:Dopamine