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Reduced plasticity and mild cognitive impairment-like deficits after entorhinal lesions in hAPP/APOE4 mice
Jean-Bastien Bott1, Brigitte Cosquer, Céline Héraud
1Laboratoire de Neurosciences Cognitives et Adaptatives, UMR 7364 CNRS, Université de Strasbourg, Strasbourg, France.
Abstract:
Mild cognitive impairment (MCI) is a clinical condition that often precedes Alzheimer disease (AD). Compared with apolipoprotein E-ε3 (APOE3), the apolipoprotein E-ε4 (APOE4) allele is associated with an increased risk of developing MCI and spatial navigation impairments. In MCI, the entorhinal cortex (EC), which is the main innervation source of the dentate gyrus, displays partial neuronal loss. We show that bilateral partial EC lesions lead to marked spatial memory deficits and reduced synaptic density in the dentate gyrus of APOE4 mice compared with APOE3 mice. Genotype and lesion status did not affect the performance in non-navigational tasks. Thus, partial EC lesions in APOE4 mice were sufficient to induce severe spatial memory impairments and synaptic loss in the dentate gyrus. In addition, lesioned APOE4 mice showed no evidence of reactional increase in cholinergic terminals density as opposed to APOE3 mice, suggesting that APOE4 interferes with the ability of the cholinergic system to respond to EC input loss. These findings provide a possible mechanism underlying the aggravating effect of APOE4 on the cognitive outcome of MCI patients.
Insights
The apolipoprotein E-ε4 (APOE4) allele worsens spatial memory deficits in mild cognitive impairment (MCI) by impairing the brain's response to entorhinal cortex (EC) damage.
Area of Science:
- Neuroscience
- Genetics
- Cognitive Science
Background:
- Mild cognitive impairment (MCI) often precedes Alzheimer's disease (AD).
- The apolipoprotein E-ε4 (APOE4) allele increases MCI and spatial navigation impairment risk compared to APOE3.
- The entorhinal cortex (EC), crucial for memory, shows neuronal loss in MCI.
Purpose of the Study:
- To investigate the impact of APOE genotype on spatial memory and synaptic plasticity following entorhinal cortex (EC) lesions.
- To explore the role of the cholinergic system in APOE4-associated cognitive decline.
Main Methods:
- Induction of bilateral partial entorhinal cortex (EC) lesions in APOE3 and APOE4 mice.
- Assessment of spatial memory performance and synaptic density in the dentate gyrus.
- Analysis of cholinergic terminal density in lesioned and non-lesioned mice.
Main Results:
- APOE4 mice with EC lesions exhibited significant spatial memory deficits and reduced dentate gyrus synaptic density compared to APOE3 mice.
- Non-navigational task performance was unaffected by genotype or lesion status.
- Lesioned APOE4 mice did not show the compensatory increase in cholinergic terminals observed in APOE3 mice.
Conclusions:
- Partial EC lesions are sufficient to cause severe spatial memory impairments and synaptic loss in APOE4 mice.
- APOE4 appears to interfere with the cholinergic system's adaptive response to EC damage.
- These findings suggest a mechanism for APOE4's exacerbating effect on cognitive outcomes in MCI.
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