Relationship: 1069



N/A, Neurodegeneration leads to Impairment, Learning and memory

Upstream event


N/A, Neurodegeneration

Downstream event


Impairment, Learning and memory

Key Event Relationship Overview


AOPs Referencing Relationship


Taxonomic Applicability


Sex Applicability


Life Stage Applicability


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 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),

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.

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







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)



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



Bihaqui et al., 2014



About 5x increase of neuronal death in hippocampus


Return to control levels in vivo and in vitro after minocycline treatment



Long Term Potentiation (LTP) was lost in Pb-treated rats


restores upon minocycline treatment




Rats exposed to Pb (100 ppm) from 24 to 80 days of age




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)



Gu et al., 2012



Response-response Relationship




Known modulating factors


Known Feedforward/Feedback loops influencing this KER


Domain of Applicability




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, 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.

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.

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.

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.