Astrocytic and Neuronal Apolipoprotein E Isoforms Differentially Affect Neuronal Excitability

Abstract

Synaptic changes and neuronal network dysfunction are among the earliest changes in Alzheimer’s disease (AD). Apolipoprotein E4 (ApoE4), the major genetic risk factor in AD, has been shown to be present at synapses and to induce hyperexcitability in mouse knock-in brain regions vulnerable to AD. ApoE in the brain is mainly generated by astrocytes, however, neurons can also produce ApoE under stress conditions such as aging. The potential synaptic function(s) of ApoE and whether the cellular source of ApoE might affect neuronal excitability remain poorly understood. Therefore, the aim of this study was to elucidate the synaptic localization and effects on neuronal activity of the two main human ApoE isoforms from different cellular sources in control and AD-like in vitro cultured neuron models. In this study ApoE is seen to localize at or near to synaptic terminals. Additionally, we detected a cellular source-specific effect of ApoE isoforms on neuronal activity measured by live cell Ca2+ imaging. Neuronal activity increases after acute but not long-term administration of ApoE4 astrocyte medium. In contrast, ApoE expressed by neurons appears to induce the highest neuronal firing rate in the presence of ApoE3, rather than ApoE4. Moreover, increased neuronal activity in APP/PS1 AD transgenic compared to wild-type neurons is seen in the absence of astrocytic ApoE and the presence of astrocytic ApoE4, but not ApoE3. In summary, ApoE can target synapses and differentially induce changes in neuronal activity depending on whether ApoE is produced by astrocytes or neurons. Astrocytic ApoE induces the strongest neuronal firing with ApoE4, while the most active and efficient neuronal activity induced by neuronal ApoE is caused by ApoE3. ApoE isoforms also differentially affect neuronal activity in AD transgenic compared to wild-type neurons.

APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases

“…ApoE is present in a subset of synapses, co-localizing to 18–36% of synapses [ 459 ]. A recent study observed a synapse-associated localization of apoE in primary neuron cultures, in which both apoE3 and apoE4 co-localize with vGlut1-positive pre-synaptic terminals [ 460 ]. ApoE co-localizes with synaptic markers in both healthy controls and AD subjects, pointing towards a not purely pathological role of apoE at synaptic terminals.…”

“…Further on, regarding astrocytic implications in neuroinflammation, sex-mediated differences in the astrocytic response towards an inflammatory stimulus have been described in primary astrocytic cell lines [ 554 , 555 ]. ApoE can target synapses and impact neuronal activity differently if released by neurons or astrocytes [ 460 ]. Live-calcium imaging techniques in vitro cultured neuron models have evidenced that neuron-released apoE induces the highest neuronal firing in the presence of apoE3 and not apoE4, whereas astrocytic-derived apoE induces the strongest neuronal firing with apoE4 [ 460 ].…”

“…ApoE can target synapses and impact neuronal activity differently if released by neurons or astrocytes [ 460 ]. Live-calcium imaging techniques in vitro cultured neuron models have evidenced that neuron-released apoE induces the highest neuronal firing in the presence of apoE3 and not apoE4, whereas astrocytic-derived apoE induces the strongest neuronal firing with apoE4 [ 460 ]. Additionally, it has been reported in APOE4 astrocytes from male but not female APOE -targeted replacement mice higher calcium hyperactivity [ 556 ].…”

Neuronal ApoE Regulates the Cell-to-Cell Transmission of α-Synuclein

“…The ApoE expressed in microglia is involved in switching between homeostatic and disease-associated phenotypes [ 57 ]. ApoE3 KI neurons show increased neuronal activity compared to ApoE4 KI neurons [ 58 ]. The overexpression of human ApoE4 in neurons results in the hyperphosphorylation of the microtubule-associated protein tau [ 54 ].…”

A multi‐hit hypothesis for an APOE4‐dependent pathophysiological state

“…However, as with overall morphology, APOE4 ‐related synaptic protein loss is exacerbated by stressors, injury, and neuronal ApoE4 expression (Buttini et al, 1999, 2000, 2010; Lin et al, 2016; Zhang et al, 2021). Similarly, in vitro studies suggest a possible loss of excitatory and inhibitory synapses and impaired maturational rate via glial‐derived ApoE4 (Konings et al, 2021; Nwabuisi‐Heath et al, 2013), supporting the importance of both glial and neuronal ApoE in synapse formation and maintenance.…”