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Apoptosis leads to N/A, Neurodegeneration
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Activation of MEK-ERK1/2 leads to deficits in learning and cognition via ROS and apoptosis||adjacent||Not Specified||Not Specified||Travis Karschnik (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
|All life stages||Moderate|
Key Event Relationship Description
In the central nervous system (CNS), neuronal apoptosis is a physiological process that is an integral part of neurogenesis, and aberrant apoptosis has been implicated in the pathogenesis of neurodegeneration (Okouchi et al., 2007).
Evidence Collection Strategy
This KER was identified as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki. The KER is referenced in publications which were cited in the originating work for the putative AOP "Activation of MEK-ERK1/2 leads to deficits in learning and cognition via ROS and apoptosis", Katherine von Stackelberg & Elizabeth Guzy & Tian Chu & Birgit Claus Henn, 2015. Exposure to Mixtures of Metals and Neurodevelopmental Outcomes: A Multidisciplinary Review Using an Adverse Outcome Pathway Framework, Risk Analysis, John Wiley & Sons, vol. 35(6), pages 971-1016, June.
Evidence Supporting this KER
During the development of the nervous system, an excessive number of neurons is produced. This massive overproduction of neurons is followed by a programmed demise of roughly one half of the originally produced cells (Okouchi et al., 2007). The precisely controlled process is referred to as naturally occurring neuronal death which is a highly conserved cellular mechanism in diverse organisms, ranging from invertebrate species such as the nematode (Okouchi et al., 2007), Caenorhabditis elegans, and insects, to nearly all of the studied vertebrate species (Mishima et al., 1999). Natural neuronal death is be lieved to mold the nervous system’s cellular structure and function (Okouchi et al., 2007).
As axons extend, they also bifurcate with each branch forming of its own growth cone, a process that is also regulated by apoptosis (Chen et al., 2020). Under normal conditions, a low level of caspase maintains a balance between growth cone attraction and repulsion and inhibits axon extension; however, in PTSD, apoptosis is enhanced in key brain regions and caspase activation alters growth cone trajectory and dendritic pruning, leading to axon misguidance and dendrite degeneration. The combined outcome of these processes is the formation of fewer or incorrect synapses in PTSD that are defective in information transmission and cause abnormalities in memory and behavior (Chen et al., 2020).
Uncertainties and Inconsistencies
While the molecular mechanisms underlying neuronal apoptosis and diabetic encephalopathy remain unresolved, it appears that diabetes-associated perturbations in the insulin/IGF system and hyperglycemia may play prominent roles (Li and Sima 2004).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
A. Petzold, et al. In vivo monitoring of neuronal loss in traumatic brain injury: a microdialysis study Brain, 134 (Pt 2) (2011), pp. 464-483
Bao J, Cao C, Zhang X, Jiang F, Nicosia SV, and Bai W. Suppression of beta-amyloid precursor protein signaling into the nucleus by estrogens mediated through complex formation between the estrogen receptor and Fe65. Mol Cell Biol 27: 1321–1333, 2007.
Chen, Xinzhao, et al. "Synapse impairment associated with enhanced apoptosis in post‐traumatic stress disorder." Synapse 74.2 (2020): e22134.
Chiueh C, Lee S, Andoh T, and Murphy D. Induction of antioxidative and antiapoptotic thioredoxin supports neuroprotective hypothesis of estrogen. Endocrine 21: 27–31, 2003.
Chiueh CC, Andoh T, Lai AR, Lai E, and Krishna G. Neuroprotective strategies in Parkinson’s disease: protection against progressive nigral damage induced by free radicals. Neurotox Res 2: 293–310, 2000.
Deigner HP, Haberkorn U, and Kinscherf R. Apoptosis modulators in the therapy of neurodegenerative diseases. Expert Opin Investig Drugs 9: 747–764, 2000.
Gandy S. Estrogen and neurodegeneration. Neurochem Res 28: 1003–1008, 2003.
Kiechle T, Dedeoglu A, Kubilus J, Kowall NW, Beal MF, Friedlander RM, Hersch SM, and Ferrante RJ. Cytochrome C and caspase-9 expression in Huntington’s disease. Neuromolec Med 1: 183–195, 2002.
Koh PO, Won CK, and Cho JH. Estradiol prevents the injury-induced decrease of Akt/glycogen synthase kinase 3beta phosphorylation. Neurosci Lett 404: 303–308, 2006.
L. Pan, et al. Functional equivalence of Brn3 POU-domain transcription factors in mouse retinal neurogenesis Development, 132 (4) (2005), pp. 703-712
Li ZG and Sima AA. C-peptide and central nervous system complications in diabetes. Exp Diabesity Res 5: 79–90, 2004.
Li ZG, Zhang W, and Sima AA. The role of impaired insulin/IGF action in primary diabetic encephalopathy. Brain Res 1037: 12–24, 2005.
Li ZG, Zhang W, Grunberger G, and Sima AA. Hippocampal neuronal apoptosis in type 1 diabetes. Brain Res 946: 221–231, 2002.
Matsubara E, Bryant-Thomas T, Pacheco Quinto J, Henry TL, Poeggeler B, Herbert D, Cruz–Sanchez F, Chyan YJ, Smith MA, Perry G, Shoji M, Abe K, Leone A, Grundke–Ikbal I, Wilson GL, Ghiso J, Williams C, Refolo LM, Pappolla MA, Chain DG, and Neria E. Melatonin increases survival and inhibits oxidative and amyloid pathology in a transgenic model of Alzheimer’s disease. J Neurochem 85: 1101–1108, 2003.
Mishima K, Tozawa T, Satoh K, Matsumoto Y, Hishikawa Y, and Okawa M. Melatonin secretion rhythm disorders in patients with senile dementia of Alzheimer’s type with disturbed sleep-waking. Biol Psychiatry 45: 417–421, 1999
Okouchi, Masahiro, et al. "Neuronal apoptosis in neurodegeneration." Antioxidants & redox signaling 9.8 (2007): 1059-1096.
P.B. Pun, et al. Low level primary blast injury in rodent brain Front. Neurol., 2 (2011), p. 19
Pappolla M, Bozner P, Soto C, Shao H, Robakis NK, Zagorski M, Frangione B, and Ghiso J. Inhibition of Alzheimer beta-fibrillogenesis by melatonin. J Biol Chem 273: 7185–7188, 1998
Pappolla MA, Simovich MJ, Bryant–Thomas T, Chyan YJ, Poeggeler B, Dubocovich M, Bick R, Perry G, Cruz–Sanchez F, and Smith MA. The neuroprotective activities of melatonin against the Alzheimer beta-protein are not mediated by melatonin membrane receptors. J Pineal Res 32: 135–142, 2002.
Rai, Nagendra Kumar, et al. "Exposure to As, Cd and Pb-mixture impairs myelin and axon development in rat brain, optic nerve and retina." Toxicology and applied pharmacology 273.2 (2013): 242-258.
Rohn TT, Rissman RA, Davis MC, Kim YE, Cotman CW, and Head E. Caspase-9 activation and caspase cleavage of tau in the Alzheimer’s disease brain. Neurobiol Dis 11: 341–354, 2002
Sanchez I, Xu CJ, Juo P, Kakizaka A, Blenis J, and Yuan J. Caspase-8 is required for cell death induced by expanded polyglutamine repeats. Neuron 22: 623–633, 1999.
Sima AA and Li ZG. The effect of C-peptide on cognitive dysfunction and hippocampal apoptosis in type 1 diabetic rats. Diabetes 54: 1497–1505, 2005.
Teng X, Sakai T, Liu L, Sakai R, Kaji R, and Fukui K. Attenuation of MPTP-induced neurotoxicity and locomotor dysfunction in Nucling-deficient mice via suppression of the apoptosome pathway. J Neurochem 97: 1126–1135, 2006.
Yao M, Nguyen TV, and Pike CJ. Estrogen regulates Bcl-w and Bim expression: role in protection against beta-amyloid peptide induced neuronal death. J Neurosci 27:1422–1433, 2007.
Zhang Y, McLaughlin R, Goodyer C, and LeBlanc A. Selective cytotoxicity of intracellular amyloid peptide1-42 through p53 and Bax in cultured primary human neurons. J Cell Biol 156: 519–529, 2002.