APOE genotype affects the pre‐synaptic compartment of glutamatergic nerve terminals

Abstract

Apolipoprotein E (APOE) genotype affects outcomes of Alzheimer’s Disease and other conditions of brain damage. Using APOE knock-in mice, we have previously shown that APOE- ε4 Targeted Replacement (TR) mice have fewer dendritic spines and reduced branching in cortical neurons. Since dendritic spines are postsynaptic sites of excitatory neurotransmission, we used APOE TR mice to examine whether APOE genotype affected the various elements of the glutamate-glutamine cycle. We found that levels of glutamine synthetase and glutamate uptake transporters were unchanged among the APOE genotypes. However, compared to APOE- ε3 TR mice, APOE-ε4 TR mice had decreased glutaminase levels (18%, p<0.05), suggesting decreased conversion of glutamine to glutamate. APOE-ε4 TR mice also had increased levels of the vesicular glutamate transporter VGLUT1 (20%, p<0.05), suggesting that APOE genotype affects presynaptic terminal composition. To address whether these changes affected normal neurotransmission, we examined the production and metabolism of glutamate and glutamine at 4–5 months and 1 year. Using high frequency 13C/1H nuclear magnetic resonance (NMR) spectroscopy, we found that APOE-ε4 TR mice have decreased production of glutamate and increased levels of glutamine. These factors may contribute to the increased risk of neurodegeneration associated with APOE-ε4, and also act as surrogate markers for AD risk.

Do glia drive synaptic and cognitive impairment in disease?

“…APOE4 may contribute to Aβ aggregation by decreasing rate of its clearance 75 . Moreover, mice that express the human APOE4 variant show fewer dendritic spines and reduced branching in cortical neurons with decreased production of glutamate from the presynaptic compartment 76 . It is interesting to note that these ApoE4 knock-in mice do not develop Aβ plaques, suggesting that APOE4 can impair synaptic plasticity and homeostasis independently of plaque formation.…”

Alzheimer's Disease Genetic Risk Factor APOE-ε4 Also Affects Normal Brain Function

“…Compared to APOE2 and APOE3 TR mice, APOE4 TR mice have altered levels of the vesicular glutamate transporter, VGLUT1 [29; 42]. These effects are related to the diet of the animals, such that a diet high in fat results in APOE4 TR mice with lowered VGLUT1 levels [29; 43], while APOE4 TR mice fed a normal diet have increased VGLUT1 levels [42]. Since apoE is a lipid transporter, fat content in the diet may alter the pathological effects of APOE4 [43].…”

“…Since apoE is a lipid transporter, fat content in the diet may alter the pathological effects of APOE4 [43]. APOE4 TR mice also have increased brain glutamine levels and decreased levels of glutaminase, the enzyme responsible for the conversion of glutamine to glutamate [42]. Interestingly, several of the pre-synaptic differences observed are related to the glutamate cycle, suggesting that APOE4 may be disrupting the normal cycling of glutamate prior to AD onset [44].…”

Young APOE4 targeted replacement mice exhibit poor spatial learning and memory, with reduced dendritic spine density in the medial entorhinal cortex

“…ApoE4 reduces dendritic complexity and spine density in vivo (Wang et al 2005;Dumanis et al 2009) and negatively affects hippocampal long-term potentiation (Trommer et al 2004;Korwek et al 2009;Chen et al 2010). APOE4 TR mice have alterations in elements of the glutamate -glutamine cycle, and exhibit a seizure phenotype correlated with abnormal cortical EEG activity, indicating a disruption in the balance of excitatory and inhibitory neurotransmission (Hunter et al 2012;Dumanis et al 2013). These reports provide compelling evidence for abnormal neuronal function in E4 mice that may lead to cognitive impairment.…”