Human apoE4-targeted replacement mice display synaptic deficits in the absence of neuropathology
Section snippets
Preparation of animals
The TR mice were created by gene targeting as described previously (Sullivan et al., 1997). Briefly, the construction of the TR mice differ from other apoE transgenic mice in that human APOE genomic fragments were used to replace the mouse Apoe gene via homologous recombination. All three lines of apoE TR mice contain chimeric genes consisting of mouse 5′ regulatory sequences continuous with mouse exon 1 (noncoding) followed by human exons (and introns) 2–4 (Sullivan et al., 1997). Thus, all
Absence of neuropathology in young human apoE TR mice
We examined age (7 month), sex (male), and genotype (apoE3 vs. apoE4) matched TR mice for signs of neurodegeneration. Using antibodies against common markers of neurodegeneration (i.e., glial fibrillary acidic protein for gliosis, tau for neurofibrillary tangles, and Aβ for amyloid deposits), we did not detect any differences in staining between the apoE3 and E4 mice (data not shown). ApoE immunoreactivity in the amygdala of E3 and E4 mice showed the same glial pattern of apoE expression as
Discussion
The amygdala is a limbic structure that plays a significant role in emotional learning, memory, and behavior (Fried et al., 2001, Hamann et al., 2002). Like other limbic structures, the amygdala is a plastic area of the brain and is responsible for mediating thalamic inputs from various sensory stimuli. Along with the hippocampus and entorhinal cortex, it is one of the first structures to show atrophy and histopathological changes characteristic of AD (Braak et al., 1993). Our studies show
Acknowledgments
We wish to thank Jason Moss for expert technical assistance. We thank Drs. Warren Strittmatter and Jim Burke for critical review of the manuscript. This work was supported by an NIA grant P50 AG05128-18, and grants from the Department of Veterans Affairs to SDM and WAW.
References (59)
- et al.
Reduced cholinergic function in normal and Alzheimer's disease brain is associated with apolipoprotein E4 genotype
Neurosci. Lett.
(1997) - et al.
Behavioural, physiological and morphological analysis of a line of apolipoprotein E knockout mouse
Neuroscience
(1998) Disturbance of neuronal plasticity is a critical pathogenetic event in Alzheimer's disease
Int. J. Dev. Neurosci.
(2001)Alzheimer's disease as a disorder of mechanisms underlying structural brain self-organization
Neuroscience
(2001)- et al.
Stable expression and secretion of apolipoproteins E3 and E4 in mouse neuroblastoma cells produces differential effects on neurite outgrowth
J. Biol. Chem.
(1995) - et al.
Early effect of ApoE-epsilon 4 allele on cognitive results in a group of highly performing subjects: the EVA study. Etude sur le Vieillissement Arteriel
Neurosci. Lett.
(1996) - et al.
Apolipoprotein (apo) E genotype and apoE concentration determine binding of normal very low density lipoproteins to HepG2 cell surface receptors
J. Lipid Res.
(1996) - et al.
Synaptic loss is accompanied by an increase in synaptic area in the dentate gyrus of aged human apolipoprotein E4 transgenic mice
Neuroscience
(2000) - et al.
Reversal of presynaptic deficits of apolipoprotein E-deficient mice in human apolipoprotein E transgenic mice
Neuroscience
(2000) - et al.
A minimally lipidated form of cell-derived apolipoprotein E exhibits isoform-specific stimulation of neurite outgrowth in the absence of exogenous lipids or lipoproteins
J. Biol. Chem.
(1998)
Evidence for normal aging of the septo-hippocampal cholinergic system in apoE (−/−) mice but impaired clearance of axonal degeneration products following injury
Exp. Neurol.
Memory deficits and cholinergic impairments in apolipoprotein E-deficient mice
Neurosci. Lett.
Impaired fear conditioning in Alzheimer's disease
Neuropsychologia
Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI
J. Lipid Res.
Apolipoprotein E isoform-specific regulation of dendritic spine morphology in apolipoprotein E transgenic mice and Alzheimer's disease patients
Neuroscience
Synaptic and neuritic alterations during the progression of Alzheimer's disease
Neurosci. Lett.
Neurodegeneration in the central nervous system of apoE-deficient mice
Exp. Neurol.
Alterations in apolipoprotein E expression during aging and neurodegeneration
Progr. Neurobiol.
Apolipoprotein E in animal models of CNS injury and in Alzheimer's disease
Trends Neurosci.
Apolipoprotein E polymorphism and Alzheimer's disease
Lancet
Increased dendritic extent in hippocampal CA1 neurons from aged F344 rats
Neurobiol. Aging
Emotional tagging of memory formation–in the search for neural mechanisms
Brain Res. Brain Res. Rev.
Targeted replacement of the mouse apolipoprotein E gene with the common human APOE3 allele enhances diet-induced hypercholesterolemia and atherosclerosis
J. Biol. Chem.
Marked regional differences of brain human apolipoprotein E expression in targeted replacement mice
Neuroscience
Synaptotagmin and synaptic transmission alterations in apolipoprotein E-deficient mice
Prog. Neuro-Psychopharmacol. Biol. Psychiatry
Differential neurotrophic effects of apolipoprotein E in aged transgenic mice
Neurosci. Lett.
Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning
J. Biol. Chem.
Mechanisms of amygdala modulation of hippocampal plasticity
J. Neurosci.
Staging of Alzheimer-related cortical destruction
Eur. Neurol.
Cited by (111)
Somatostatin and the pathophysiology of Alzheimer's disease
2024, Ageing Research ReviewsApoE4 attenuates cortical neuronal activity in young behaving apoE4 rats
2021, Neurobiology of DiseaseCognitively normal APOE ε4 carriers have specific elevation of CSF SNAP-25
2021, Neurobiology of AgingCitation Excerpt :This includes reductions of key presynaptic proteins (Tannenberg et al., 2006) and disruptions of presynaptic vesicular release and glutamine-to-glutamate production (Dumanis et al., 2013). Postsynaptic effects include disruptions of reelin-mediated long-term potentiation and plasticity (Weeber et al., 2002) and reductions in dendritic spine density and complexity (Dumanis et al., 2009; Jain et al., 2013; Wang et al., 2005) that may be further amplified in the presence of amyloid plaques (Holtzman et al., 2000). However, the relationship between APOE genotype and pre- or postsynaptic dysfunction in cognitively normal older adults remains unclear.
Dysfunction of the SNARE complex in neurological and psychiatric disorders
2021, Pharmacological ResearchDetection of early Alzheimer's disease-like molecular alterations in a mouse model expressing human ApoE4
2023, Journal of Neurochemistry