Age-dependent enhancement of hippocampal long-term potentiation in knock-in mice expressing human apolipoprotein E4 instead of mouse apolipoprotein E

doi:10.1016/j.neulet.2004.07.084

Neuroscience Letters

Volume 369, Issue 3, 21 October 2004, Pages 173-178

https://doi.org/10.1016/j.neulet.2004.07.084 Get rights and content

Abstract

Human apolipoprotein E (apoE) comprises three isoforms, apoE2, apoE3 and apoE4, and apoE4 has been reported as a risk factor of Alzheimer's disease (AD). One of the clinical symptoms of AD is disorder of memory that has been suggested to be related with synaptic plasticity such as long-term potentiation (LTP). Here, we show the enhancement of hippocampal LTP at younger age in knock-in mice lacking mouse apoE, but instead expressing human apoE4. The enhancement of LTP in apoE4 knock-in mice is age-dependent, and it disappears in adult apoE4 knock-in mice. In apoE3 knock-in mice LTP is unaltered, thus human apoE4, but not apoE3, specifically modulates synaptic plasticity at younger age. Since basal synaptic transmission and distribution of glutamate receptors, as well as presynaptic functions, are intact in apoE4 knock-in mice, postsynaptic functional modification of LTP through lipid homeostasis is suggested. ApoE4 knock-in mice would be a useful animal model of human apoE4 carriers, and our finding that LTP is enhanced in younger apoE4 knock-in mice is in accord with the previous report showing higher intelligence in young human apoE4 carriers.

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Acknowledgments

This study was supported by grants-in-aid from the Ministry of Education, Science, Sports, Culture and Technology of Japan. We are grateful to Ayako M. Watabe for helpful comments on the manuscript and to Misa Shimuta for technical advice and comments on the manuscript.

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Apolipoprotein E, Receptors, and Modulation of Alzheimer's Disease
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Apolipoprotein E (apoE) is a lipid carrier in both the peripheral and the central nervous systems. Lipid-loaded apoE lipoprotein particles bind to several cell surface receptors to support membrane homeostasis and injury repair in the brain. Considering prevalence and relative risk magnitude, the ε4 allele of the APOE gene is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). ApoE4 contributes to AD pathogenesis by modulating multiple pathways, including but not limited to the metabolism, aggregation, and toxicity of amyloid-β peptide, tauopathy, synaptic plasticity, lipid transport, glucose metabolism, mitochondrial function, vascular integrity, and neuroinflammation. Emerging knowledge on apoE-related pathways in the pathophysiology of AD presents new opportunities for AD therapy. We describe the biochemical and biological features of apoE and apoE receptors in the central nervous system. We also discuss the evidence and mechanisms addressing differential effects of apoE isoforms and the role of apoE receptors in AD pathogenesis, with a particular emphasis on the clinical and preclinical studies related to amyloid-β pathology. Finally, we summarize the current strategies of AD therapy targeting apoE, and postulate that effective strategies require an apoE isoform–specific approach.
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Intriguingly, Mondadori et al. (2007) have also reported an association of ApoE4 with better episodic memory compared to ApoE2 and ApoE3 in a sample of 340 young adults (age = 22). Considered in tandem with previous evidence where ApoE4 has been associated with higher IQ scores in younger adults (Yu et al., 2000) and enhancement of hippocampal long-term potentiation (Kitamura et al., 2004), it could be hypothesised that ApoE4 mediates neurodevelopmental resilience (Oría et al., 2005) (Brazil study) and enhanced intellectual function in children and young adults. It is thus possible that, through an interaction with age, the effect of ApoE4 transitions from a quiescent or even neuroprotective role from childhood to young adulthood before exerting a deleterious effect on cognition (Lothian Birth Cohort 1921) (Schiepers et al., 2012) and brain morphology in later life.
The last decade has witnessed a proliferation of neuroimaging studies characterising brain changes associated with Alzheimer’s disease (AD), where both widespread atrophy and ‘signature’ brain regions have been implicated. In parallel, a prolonged latency period has been established in AD, with abnormal cerebral changes beginning many years before symptom onset. This raises the possibility of early therapeutic intervention, even before symptoms, when treatments could have the greatest effect on disease-course modification. Two important prerequisites of this endeavour are (1) accurate characterisation or risk stratification and (2) monitoring of progression using neuroimaging outcomes as a surrogate biomarker in those without symptoms but who will develop AD, here referred to as preclinical AD. Structural neuroimaging modalities have been used to identify brain changes related to risk factors for AD, such as familial genetic mutations, risk genes (for example apolipoprotein epsilon-4 allele), and/or family history. In this review, we summarise structural imaging findings in preclinical AD. Overall, the literature suggests early vulnerability in characteristic regions, such as the medial temporal lobe structures and the precuneus, as well as white matter tracts in the fornix, cingulum and corpus callosum. We conclude that while structural markers are promising, more research and validation studies are needed before future secondary prevention trials can adopt structural imaging biomarkers as either stratification or surrogate biomarkers.
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Citation Excerpt :
The ϵ4 allele has indeed been associated with increased hippocampal activation during both episodic encoding and retrieval [26,27]. In animal studies, young mice expressing the human form of APOE ϵ4 have shown enhanced hippocampal long term potentiation, a process important for memory function [65]. It is possible that hippocampal function during performance of spatial tasks also differs between ϵ4 carriers and non-carriers, which should be assessed in future studies.
The apolipoprotein E (APOE) ϵ4 allele is known to be a major genetic risk factor for Alzheimer’s disease (AD). It has been linked to especially episodic memory decline and hippocampal atrophy in both healthy and demented elderly populations. In young adults, ϵ4 carriers have shown better performance in episodic memory compared to non-carriers. Spatial memory, however, has not been thoroughly assessed in relation to APOE in spite of its dependence on the hippocampus. In this study, we assessed the effect of APOE genotype on a variety of spatial and episodic memory tasks as well as hippocampal volume assessed through manual tracing in a sample of young adults (N = 123). We also assessed whether potential effects were modulated by sex. The presence of one or more ϵ4 alleles had positive effects on spatial function and memory and object location memory, but no effect on word recognition. Men were superior to women in spatial function and memory but there were no sex differences in the other tasks. In spite of APOE ϵ4 carriers having superior performance in several memory tasks, no difference was found as a function of APOE genotype in hippocampal volume. To our knowledge, this study is the first to show that APOE ϵ4 has a positive effect on spatial ability in young adults.
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Apolipoprotein E (apoE) is a key protein linked to the pathogenesis of Alzheimer’s disease (AD) beyond its central roles in lipid metabolism. Among the three human APOE gene alleles, APOE4 is the strongest genetic risk factor for AD, while APOE2 is protective. Although apoE isoforms regulate amyloid-β (Aβ) metabolism with apoE4 exacerbating Aβ deposition, emerging evidence indicates that apoE isoforms influence cognition through various pathways in Aβ-independent manners. ApoE isoforms also regulate neuronal cholesterol metabolism, brain glucose metabolism, mitochondrial functions, cerebrovascular system, and immune responses, which substantially contribute to AD pathogenesis. Therefore, apoE isoforms likely regulate critical pathways influencing brain homeostasis and cognition independent of Aβ-related effects. Better understanding of the link between apoE isoforms and Aβ-independent mechanisms in AD pathogenesis should allow us to define novel targets for AD therapy.
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Alzheimer’s disease (AD) is clinically characterized with progressive memory loss and cognitive decline. Synaptic dysfunction is an early pathological feature that occurs prior to neurodegeneration and memory dysfunction. Mounting evidence suggests that aggregation of amyloid-β (Aβ) and hyperphosphorylated tau leads to synaptic deficits and neurodegeneration, thereby to memory loss. Among the established genetic risk factors for AD, the ɛ4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor. We and others previously demonstrated that apoE regulates Aβ aggregation and clearance in an isoform-dependent manner. While the effect of apoE on Aβ may explain how apoE isoforms differentially affect AD pathogenesis, there are also other underexplored pathogenic mechanisms. They include differential effects of apoE on cerebral energy metabolism, neuroinflammation, neurovascular function, neurogenesis, and synaptic plasticity. ApoE is a major carrier of cholesterols that are required for neuronal activity and injury repair in the brain. Although there are a few conflicting findings and the underlying mechanism is still unclear, several lines of studies demonstrated that apoE4 leads to synaptic deficits and impairment in long-term potentiation, memory and cognition. In this review, we summarize current understanding of apoE function in the brain, with a particular emphasis on its role in synaptic plasticity and the underlying cellular and molecular mechanisms, involving low-density lipoprotein receptor-related protein 1 (LRP1), syndecan, and LRP8/ApoER2.

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PlenaryAge-dependent enhancement of hippocampal long-term potentiation in knock-in mice expressing human apolipoprotein E4 instead of mouse apolipoprotein E

Abstract

Section snippets

Acknowledgments

Neuroscience

Neuroscience

Neuroscience

Mol. Cell. Neurosci.

Neurobiol. Aging

Biochim. Biophys. Acta

J. Biol. Chem.

Neurosci. Lett.

Altered cholesterol metabolism in human apolipoprotein E4 knock-in mice

Hum. Mol. Genet.

Cholesterol is increased in the exofacial leaflet of synaptic plasma membranes of human apolipoprotein E4 knock-in mice

NeuroReport

Plenary
Age-dependent enhancement of hippocampal long-term potentiation in knock-in mice expressing human apolipoprotein E4 instead of mouse apolipoprotein E