Cellular Specificity and Inter-cellular Coordination in the Brain Bioenergetic System: Implications for Aging and Neurodegeneration

Abstract

As an organ with a highly heterogenous cellular composition, the brain has a bioenergetic system that is more complex than peripheral tissues. Such complexities are not only due to the diverse bioenergetic phenotypes of a variety of cell types that differentially contribute to the metabolic profile of the brain, but also originate from the bidirectional metabolic communications and coupling across cell types. While brain energy metabolism and mitochondrial function have been extensively investigated in aging and age-associated neurodegenerative disorders, the role of various cell types and their inter-cellular communications in regulating brain metabolic and synaptic functions remains elusive. In this review, we summarize recent advances in differentiating bioenergetic phenotypes of neurons, astrocytes, and microglia in the context of their functional specificity, and their metabolic shifts upon aging and pathological conditions. Moreover, the metabolic coordination between the two most abundant cell populations in brain, neurons and astrocytes, is discussed regarding how they jointly establish a dynamic and responsive system to maintain brain bioenergetic homeostasis and to combat against threats such as oxidative stress, lipid toxicity, and neuroinflammation. Elucidating the mechanisms by which brain cells with distinctive bioenergetic phenotypes individually and collectively shape the bioenergetic system of the brain will provide rationale for spatiotemporally precise interventions to sustain a metabolic equilibrium that is resilient against synaptic dysfunction in aging and neurodegeneration.

ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism

“…Astrocytes are known to promote neuronal function via various mechanisms, including fuel and cholesterol supply, release of neurotrophic factors, and donation of mitochondria ( Hayakawa et al, 2016 ; Qi et al, 2020 ). Our results indicate that ApoE4 impairs the bioenergetic and synaptic support of astrocyte to neurons, and the enhancement of neuronal bioenergetics is dependent on the clearance of neuronal lipids, thus suggesting an unappreciated mechanistic connection between ApoE4 and neuronal mitochondrial dysfunction via inter-cellular coupling of lipid metabolism.…”

Transcriptomic Analysis of Human Astrocytes In Vitro Reveals Hypoxia-Induced Mitochondrial Dysfunction, Modulation of Metabolism, and Dysregulation of the Immune Response

“…While some components of the inflammatory response are neuroprotective, increased levels of neuroinflammation are associated with neuronal dysfunction in AD [ 47 ], ALS [ 48 ], and PD [ 49 ]. Evidence from in vitro and in vivo models suggests that neuroinflammation increases the production of oxidative species, disrupts metabolic processes, impacts neuronal function, and causes further glial activation, as reviewed [ 50 , 51 , 52 ]. In the current study, we demonstrate astrocytes respond to hypoxia by significantly upregulating expression of genes associated with immune function.…”

Antioxidant and Neuroprotective Effects Induced by Cannabidiol and Cannabigerol in Rat CTX-TNA2 Astrocytes and Isolated Cortexes

“…As the most abundant cell type in the brain, the astrocytes have gained enormous interest in recent decades as a potential target for neurotherapies, due to their essential and pleiotropic roles in brain physiology and pathology. They provide critical metabolic and structural support to neurons [12] and their metabolic coordination with neurons is crucial to maintain brain bioenergetic homeostasis and to combat threats such as oxidative stress [13]. Oxidative stress is involved in the pathophysiology of numerous diseases of the nervous system.…”