Cellular stress from excitatory neurotransmission contributes to cholesterol loss in hippocampal neurons aging in vitro

In vitro aging promotes endoplasmic reticulum (ER)-mitochondria Ca 2+ cross talk and loss of store-operated Ca 2+ entry (SOCE) in rat hippocampal neurons

“…These results have been obtained in an in vitro model of aging and, therefore, may not reflect entirely the physiological aging of the brain. However, in support of the findings, it has been previously shown that long-term cultured rat hippocampal neurons acquire important hallmarks of neuronal aging in vivo including ROS accumulation, lipofuscin granules, heterochromatic foci, activation of pJNK and p53/p21 pathways and loss of cholesterol among others [1,3,4]. Therefore, the remodeling of subcellular Ca 2+ in aging neurons reported here may contribute to cognitive decline and the susceptibility to neuron cell death that is characteristic of the elderly.…”

“…Interestingly, some of these changes are mimicked in vitro after longterm culture of rat hippocampal neurons [1,2]. In fact, after several weeks in culture, rat hippocampal neurons display important hallmarks of neuronal aging in vivo including accumulation of reactive oxygen species (ROS), lipofuscin granules, heterochromatic foci, activation of the Jun N-terminal protein kinase (pJNK) and p53/p21 pathways, gradual loss of cholesterol, and, as stated above, changes in Ca 2+ channel density and NMDA receptor expression [1][2][3][4][5]. Accordingly, long-term cultures of hippocampal neurons may provide a suitable model for investigating Ca 2+ remodeling in aging hippocampal neurons.…”

Lipid dynamics at dendritic spines

“…Pioneer work showed that acute cyclodextrin-mediated removal of membrane cholesterol blocks LTP in the hippocampus (Koudinov and Koudinova, 2001; Frank et al, 2008). On the other hand, excitatory neurotransmission, chronic and acute, induces cholesterol loss from synapses, which is recovered after stimuli (Sodero et al, 2011, 2012). In the aging brain, lifelong lasting synaptic activity and concomitant metabolic stress contributes to a moderate but irreversible loss of membrane cholesterol (Sodero et al, 2011), which is thought to underlie cognitive deficits present at this stage of life (Martin et al, 2014).…”

Sphingomyelin upregulation in mature neurons contributes to TrkB activity by Rac1 endocytosis

“…In fact, during terminal differentiation the transcription of the cyp46A1 gene responsible for cholesterol loss is increased (Martin et al, 2008). Also, others have demonstrated the upregulation of the cyp46 gene by reactive oxygen species, which certainly accumulate once synaptic activity is established and also over time in neurons (Martin et al, 2009;Sodero et al, 2010). It is possible that different factors that accumulate during neuronal activity (e.g.…”