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Relationship: 1069
Title
N/A, Neurodegeneration leads to Impairment, Learning and memory
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
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Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development leads to neurodegeneration with impairment in learning and memory in aging | adjacent | High | Florianne Tschudi-Monnet (send email) | Open for citation & comment | WPHA/WNT Endorsed | |
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 Do not cite |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
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Unspecific | Moderate |
Life Stage Applicability
Term | Evidence |
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Old Age | Moderate |
Key Event Relationship Description
Animal models of neurodegenerative diseases, in particular Alzheimer's disease, contributed to the elucidation of the link between amyloid protein and tau hyperphosphorylation and cognitive deficits. Bilateral injections of amyloid-b peptide in the frontal cortex of rats leads to progressive decline in memory and neurodegeneration in hippocampus (for review see Eslamizade et al., 2016). Recent findings have shown that soluble forms of Ab rather than insoluble forms (fibrils and plaques) are associated with memory impairment in early stages of Alzheimer's disease (for review see Salgado-Puga and Pena-Ortega, 2015). Several lines of evidence suggest that the small oligomeric forms of Ab and tau may act synergistically to promote synaptic dysfunction in Alzheimer's disease (for review see Guerrerro-Minoz et al., 2015). Some reports proposed the concept of imbalance between production and clearance of Ab42 and related Ab peptides, as an initiating factor inducing hyperphosphorylation of tau and leading to neuritic dystrophy and synaptic dysfunction (for review see Selkoe and Hardy, 2016). Recent trials of three different antibodies against amyloid peptides have suggested a slowing of cognitive decline in post hoc analyses of mild Alzheimer subjects (for review see Selkoe and Hardy, 2016). Therefore cognitive deficits may be related to the level and extent of classical Alzheimer pathology landmarks, but it is also influenced by neurodegeneration (for review see Braskie and Thompson, 2013). Indeed decreased hippocampal volume due to widespread neurodegeneration and visualized by neuroimaging appears to be a significant predictor of memory decline (for review see Braskie and Thompson, 2016).
Evidence Collection Strategy
This KER was developed, in part, 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.
In July 2023 updates were made to the then empty Taxonomic, Sex, and Life Stage Applicability fields and in the Empirical Evidence field with the addition of Wozniak et al., (2004), Allison et al., (2021), and Huang et al., (2012) studies.
Evidence Supporting this KER
Biological Plausibility
It is well accepted that impairment of cell function or cell loss in hippocampus will interfere with memory processes, since the hippocampus plays a key role in memory (Barker and Warburton, 2011). In Alzheimer's disease, hippocampus and entorhinal cortex are affected early in the disease process and cognitive deficit is correlated with brain atrophy (for review Braskie and Thompson, 2013).
Empirical Evidence
Include consideration of temporal concordance here
Pre-natal and post-natal Pb exposure affects the hippocampus and the frontal cortex (Schneider et al., 2012). Rats exposed to Pb exhibit microglial activation, and upregulation of the level of IL-1b, TNF-a and iNOS, and these pro-inflammatory factors may cause hippocampal neuronal injury as well as Long Term Potentiation (LTP) deficits, These results suggest a direct link between Pb-induced neuroinflammation, neurodegeneration in hippocampus, and memory deficit (Liu et al., 2012). These effects are reversed by minocycline, an antibiotic which decreases microglial activation, strengthening the link between neuroinflammation, neurodegeneration and memory impairment. In epidemiological studies of adults, cumulative lifetime exposure to Pb has been associated with accelerated declines in cognition (Bakulski et al., 2012). In a study aiming at determining whether serum trace metals are related to abnormal cognition in Alzheimer's disease, it was found that serum Pb levels were significantly negatively correlated with verbal memory scores (Park et al., 2014). Cognitive impaiment was observed in mice exposed to Pb as infants but not as adults, suggesting that a window of vulnerability to Pb neurotoxicity can influence Alzheimer pathogenesis and cognitive decline in old age (Bihaqui et al., 2014). Human Tg-SWDI APP transgenic mice, which over-express amyloid plaques at age of 2-3 months, received oral gavage of 50 mg/kg of Pb once daily for 6 weeks. They showed a significant increase of Abeta in the CSF, brain cortex and hippocampus associated to impaired spatial learning ability, suggesting that Pb facilitates Abeta fibril formation and participate in deposition of amyloid plaques (Gu et al., 2012),
Wozniak et al., (2004) demonstrated that exposure of infant mice to EtOH on a single postnatal day (P7) induced extensive apoptotic neurodegeneration in the developing brain, and subsequent spatial learning and memory impairments that are very severe at P30, less severe if testing is first performed at P75, and minimal in later adulthood. In adulthood, working memory performance was also subtly compromised in EtOH-treated mice in a gender-dependent fashion, with the male EtOH mice being functionally impaired.
Allison et al., (2021) demonstrated that the deleterious effects of AD-related pathophysiology (i.e., higher levels of CSF ptau181/Aβ42) on verbal learning and memory performance depend on the degree of global atrophy present. More specifically, individuals with a greater degree of global atrophy evidenced similar rates of decline regardless of the degree of AD pathophysiology present. In contrast, in individuals with larger global brain volumes, the presence of preclinical Alzheimer's disease was associated with steeper declines in verbal learning and memory. These findings suggest that the presence of AD biomarkers, global atrophy, or both global atrophy and AD biomarkers are all associated with greater verbal learning and memory decline in a sample of late middle-aged adults.
Huang et al., (2012) findings indicated that exposure of P7 rats to ketamine leads to accelerated widespread neurodegeneration in the hippocampus. Suppression of p-PKCγ and p-ERK might be involved in neurologic damage, and this neurodegeneration could cause subsequent spatial learning abnormalities in adulthood.
Uncertainties and Inconsistencies
There are some inconsistencies regarding the time of exposure. Some papers clearly show that early Pb exposure increases amyloid and tau pathology and cognitive decline in aging. But few studies have addressed this complex question by using an ad hoc experimental design. Other studies have descibed the effects of lifetime or long-term exposure on cognitive functions but without a precise desciption of exposure onset and duration.
Known modulating factors
Quantitative Understanding of the Linkage
Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?
Endpoints relevant for KEup Neurodegeneration in hippocampus and cortex |
Endpoints relevant for KEdown Impairment of learning and memory |
Model and treatments |
Reference |
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0.5 -1x increase in amyloid peptides accumulation if early postnatal exposure |
Decrease in cognitive functions (Morris water maze, Y maze testing for spatial memory and memory, a hippocampus -dependent task)
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Mice exposed to Pb 0.2% in drinking water from PND 1 to 20
or from PND 1-20 and from 7-9 months of age
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Bihaqui et al., 2014
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About 5x increase of neuronal death in hippocampus
Return to control levels in vivo and in vitro after minocycline treatment
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Long Term Potentiation (LTP) was lost in Pb-treated rats and restores upon minocycline treatment
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Rats exposed to Pb (100 ppm) from 24 to 80 days of age
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Liu et al., 2012 |
About 2x more Abeta1-40 and of Abeta1-42 in CSF, cortex and hippocampus and 2x more amyloid plaque load than control
Pb co-localized with amyloid plaques. |
Impaired spatial learning ability (Morris maze) |
Human Tg-SWDI APP mice received by oral gavage 50mg/kg Pb once daily for 6 weeks.
Pb level in brain 60 microg/dL (similar level than those found in children, Gu et al., 2011)
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Gu et al., 2012 |
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Response-response Relationship
Time-scale
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
References
Allison, Samantha L., et al. "Neurodegeneration, Alzheimer's disease biomarkers, and longitudinal verbal learning and memory performance in late middle age." Neurobiology of aging 102 (2021): 151-160.
Bakulski KM, Park SK, Weisskopf MG, Tucker KL, Sparrow D, Spiro A, 3rd, et al. 2014. Lead exposure, B vitamins, and plasma homocysteine in men 55 years of age and older: the VA normative aging study. Environ Health Perspect 122(10): 1066-1074.
Barker GR, Warburton EC. 2011. When is the hippocampus involved in recognition memory? J Neurosci 31(29): 10721-10731.
Bihaqi SW, Bahmani A, Subaiea GM, Zawia NH. 2014. Infantile exposure to lead and late-age cognitive decline: relevance to AD. Alzheimer's & dementia : the journal of the Alzheimer's Association 10(2): 187-195.
Braskie MN, Thompson PM. 2013. Understanding cognitive deficits in Alzheimer's disease based on neuroimaging findings. Trends in cognitive sciences 17(10): 510-516.
Eslamizade MJ, Madjd Z, Rasoolijazi H, Saffarzadeh F, Pirhajati V, Aligholi H, et al. 2016. Impaired Memory and Evidence of Histopathology in CA1 Pyramidal Neurons through Injection of Abeta1-42 Peptides into the Frontal Cortices of Rat. Basic and clinical neuroscience 7(1): 31-41.
Gu H, Robison G, Hong L, Barrea R, Wei X, Farlow MR, et al. 2012. Increased beta-amyloid deposition in Tg-SWDI transgenic mouse brain following in vivo lead exposure. Toxicol Lett 213(2): 211-219.
Gu H, Wei X, Monnot AD, Fontanilla CV, Behl M, Farlow MR, et al. 2011. Lead exposure increases levels of beta-amyloid in the brain and CSF and inhibits LRP1 expression in APP transgenic mice. Neurosci Lett 490(1): 16-20.
Guerrero-Munoz MJ, Gerson J, Castillo-Carranza DL. 2015. Tau Oligomers: The Toxic Player at Synapses in Alzheimer's Disease. Frontiers in cellular neuroscience 9: 464.
Huang, Lining, et al. "Ketamine potentiates hippocampal neurodegeneration and persistent learning and memory impairment through the PKCγ–ERK signaling pathway in the developing brain." Brain research 1476 (2012): 164-171.
Liu MC, Liu XQ, Wang W, Shen XF, Che HL, Guo YY, et al. 2012. Involvement of microglia activation in the lead induced long-term potentiation impairment. PLoS One 7(8): e43924.
Park JH, Lee DW, Park KS, Joung H. 2014. Serum trace metal levels in Alzheimer's disease and normal control groups. American journal of Alzheimer's disease and other dementias 29(1): 76-83.
Salgado-Puga K, Pena-Ortega F. 2015. Cellular and network mechanisms underlying memory impairment induced by amyloid beta protein. Protein and peptide letters 22(4): 303-321.
Schneider JS, Anderson DW, Talsania K, Mettil W, Vadigepalli R. 2012. Effects of developmental lead exposure on the hippocampal transcriptome: influences of sex, developmental period, and lead exposure level. Toxicol Sci 129(1): 108-125.
Selkoe DJ, Hardy J. 2016. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO molecular medicine 8(6): 595-608.
Wozniak, David F., et al. "Apoptotic neurodegeneration induced by ethanol in neonatal mice is associated with profound learning/memory deficits in juveniles followed by progressive functional recovery in adults." Neurobiology of disease 17.3 (2004): 403-414.