Energy Metabolism Decline in the Aging Brain-Pathogenesis of Neurodegenerative Disorders

Abstract

There is a growing body of evidencethat indicates that the aging of the brain results from the decline of energy metabolism. In particular, the neuronal metabolism of glucose declines steadily, resulting in a growing deficit of adenosine triphosphate (ATP) production-which, in turn, limits glucose access. This vicious circle of energy metabolism at the cellular level is evoked by a rising deficiency of nicotinamide adenine dinucleotide (NAD) in the mitochondrial salvage pathway and subsequent impairment of the Krebs cycle. A decreasing NAD level also impoverishes the activity of NAD-dependent enzymes that augments genetic errors and initiate processes of neuronal degeneration and death.This sequence of events is characteristic of several brain structures in which neurons have the highest energy metabolism. Neurons of the cerebral cortex and basal ganglia with long unmyelinated axons and these with numerous synaptic junctions are particularly prone to senescence and neurodegeneration. Unfortunately, functional deficits of neurodegeneration are initially well-compensated, therefore, clinical symptoms are recognized too late when the damages to the brain structures are already irreversible. Therefore, future treatment strategies in neurodegenerative disorders should focus on energy metabolism and compensation age-related NAD deficit in neurons. This review summarizes the complex interrelationships between metabolic processes on the systemic and cellular levels and provides directions on how to reduce the risk of neurodegeneration and protect the elderly against neurodegenerative diseases.

Keywords: brain aging; energy metabolism; neurodegeneration; neurodegenerative disorders.

Figure 1

Simplified diagram presenting participation of the ATP in glycolysis—the input pathway in energy metabolism in neurons (for review see Reference [45]). The ATP produced in the mitochondrial process of oxidative phosphorylation is used in neurons as the rate-limiting factor of glycolysis. In this entry process, each molecule of glucose 6-phosphate is broken down into two molecules of pyruvate, which are then used as a source of energy.The chronic decline in ATP production results in neuronal insensitivity to glucose that eventually terminates the cellular energy metabolism.

Figure 2

Model of the nigrostriatal interaction showing the physiology (A) and pathophysiology (B) of the striatum that may cause Parkinson’s disease [100]. In physiological conditions, the interaction is determined by the activity-dependent continuous turnover of GABAergic interneurons of the striatum. The fast-spiking interneurons (FSI) are particularly susceptible to apoptosis, thus, the physiological function of the striatum requires the continuous exchange of these interneurons. Normal activity of the striatum that is characterized by an elevated level of neurotransmitters (mostly GABA) and the glia-derived neurotrophic factor (GDNF) intensifies proliferation and migration of stem cells to the striatum. Both GABA and GDNF are chemoattractants for progenitor cells. The subventricular zone (SVZ) is a specialized brain area containing self-renewing GFAP⁺ astrocytes functioning as neural stem cells that generate new interneurons in both the striatum and olfactory bulbs throughout life. Age-related decline inneurogenesis is followed by a decline in the nigrostriatal interaction resulting in progressive withdrawal and eventually, disconnection of the dopaminergic input from the substantia nigra pars compacta (SNpc). This initiates a ’vicious circle’ cascade of pathological events resulting in a devastating decline of nigrostriatal interaction that leads to fatal damage of the FSI turnover and neurodegeneration of the DOPA neurons of the SNpc. In this pathological state, the striatum loses its control over the pallidal output, and clinical symptoms of Parkinson’s disease such as hypokinesia and rigidity are observed. The model reproduced with permission from Błaszczyk 2017 [131]. Copyright 2017 Acta Neurobiologia Experimentalis.