Contribution of astrocytes to metabolic dysfunction in the Alzheimer’s disease brain

Abstract

Historically considered as accessory cells to neurons, there is an increasing interest in the role of astrocytes in normal and pathological conditions. Astrocytes are involved in neurotransmitter recycling, antioxidant supply, ion buffering and neuroinflammation, i.e. a lot of the same pathways that go astray in Alzheimer’s disease (AD). AD remains the leading cause of dementia in the elderly, one for which there is still no cure. Efforts in AD drug development have largely focused on treating neuronal pathologies that appear relatively late in the disease. The neuroenergetic hypothesis, however, focuses on the early event of glucose hypometabolism in AD, where astrocytes play a key role, caused by an imbalanced neuron-astrocyte lactate shuttle. This further results in a state of oxidative stress and neuroinflammation, thereby compromising the integrity of astrocyte-neuron interaction. Compromised astrocytic energetics also enhance amyloid generation, further increasing the severity of the disease. Additionally, apolipoprotein E (APOE), the major genetic risk factor for AD, is predominantly secreted by astrocytes and plays a critical role in amyloid clearance and regulates glucose metabolism in an amyloid-independent manner. Thus, boosting the neuroprotective properties of astrocytes has potential applications in delaying the onset and progression of AD. This review explores how the metabolic dysfunction arising from astrocytes acts as a trigger for the development of AD.

Lipid metabolism in astrocytic structure and function

“…As pyruvate flux into the mitochondria is regulated by the mitochondrial pyruvate carrier (MPC), the authors suggest that this is an essential regulatory control point between basal respiration and gluconeogenesis in astrocytes. Therefore, this data suggests that modulation of pathways such as gluconeogenesis may have therapeutic potential in neurological diseases where there is a significant metabolic component such as Alzheimer's disease (AD, see Zulfiqar et al for a recent review see [21]). For example, astrocytes expressing the E4 allele of Apo-lipoprotein E (APOE), a genetic risk factor for AD, were shown to have increased glucose flux via the pentose phosphate pathway (PPP).…”

“…However, in iPSCs, GW0742 did not protect against pro-inflammatory activation and in the mouse model, astrogliosis was unaffected, indicating that increasing FAO does not reverse the metabolic deficit fully. This may be because astrocyte metabolic adaptation to fatty acid dependent respiration in times of glucose hypometabolism (as observed in AD for example [21] comes at a cost. Recent work in primary astrocytes has suggested that glucose starvation leads to activation of 5' adenosine monophosphate-activated protein kinase.…”

Astrocytes as Key Regulators of Brain Energy Metabolism: New Therapeutic Perspectives

“…In addition to the historical description of the pathology that include β amyloid plaques and hyperphosphorylated tau in the brain, it is characterized by clear mitochondrial and metabolic impairments (Butterfield and Halliwell, 2019). Hence, AD can be considered as a metabolic disease with impairment in mitochondrial bioenergetics, as well as glucose brain import and metabolism (Zulfiqar et al, 2019).…”

A Novel, Multi-Faceted Perception of Lactate in Neurology

“…Furthermore, the observations of Harris et al (2019) suggest that lactate production may be required for memory acquisition but not retrieval. Hence, boosting the neuroprotective properties of astrocytes (by boosting lactate production of astrocytes) has potential applications in delaying the onset and progression of AD, as originally proposed by Demetrius et al (2015) and summarized in a review by Zulfiqar et al (2019). Furthermore, glucose hypometabolism is typically observed in AD.…”