Authored by Robert Zorec*
Introduction
Alzheimer disease (AD) is a common neurodegenerative disease, contributing to 60-70 % to all cases of dementia, which, according to the World health organization, currently represents 50 million people worldwide. AD manifests in the deterioration of cognitive functions, representing a burden for the patients, families and the society as a whole, yet there are no effective treatments. This likely arises from the lack of understanding the primary mechanisms that lead to the demise of neurons in AD. It is likely that neurodegeneration is secondary to the impairment of key homeostatic mechanisms, which are carried out by neuroglia. Here we highlight the role of astrocytes, abundant neuroglial cells in the central nervous system, providing metabolic support to neuronal networks in the form of aerobic glycolysis. Future therapies should target glycolysis regulation, as this process is impaired in AD.
Alzheimer disease (AD), noradrenergic system and astrocytes
Currently there is no effective treatment for AD, arguably the most common form of neurodegeneration, which leads to cognitive impairment. At tissue level in the central nervous system (CNS), the hallmarks of AD are extracellular deposits of fibrillar β-amyloid (Aβ, senile or neuritic plaques) and intraneuronal accumulation of neurofibrillary tangles consisting of Tau protein aggregates [1]. These are thought to elicit a slow gradual neuron loss decade(s) before the onset of the earliest clinical symptoms [2]. In brief, current view posits that neurodegeneration in AD reflects neuronspecific deficits.
However, the primary reason for the initiation of neurodegeneration may well be due to a failure in neuroglial cells, which maintain CNS homoeostasis [3]. The role of neuroglia in pathological processes was first noted by Alois Alzheimer himself, who found that glia populated senile plaques were in close contact with damaged neurons [4,5]. In humans, post-mortem AD tissue exhibits astroglial hypertrophy with overexpressed levels of glial fibrillary acidic protein (GFAP), a state termed reactive gliosis [6], which may represent a protective, but sometimes even a neurotoxic cell entity in the evolution of disease [7].
There are several hypotheses explaining the mechanism of AD development, including mutations in amyloid precursor protein or upstream sorting proteins, impairment of neuron functioning (cholinergic, noradrenergic (Locus coeruleus, LC), or glutamatergic), neuroinflamation and energy handling [8]. However, the link between astroglial failure and AD is less clear. An interesting perspective arises from the concept of “cognitive reserve”, defined as the degree of functional impairment in response to neuropathologic events, i.e. a similar extent of brain damage may in different subjects result in different cognitive outcomes [9,10]. It has two components: the neural reserve, represented by neural networks opposing pathology, and neural compensation, which reflects in the defensive reaction mounted in response to pathology. Both components are regulated by noradrenergic innervation and involve astroglia. The “neural reserve” has been tested in a study involving 165 patients, monitored annually by 19 cognitive tests [11]. Post-mortem neuropathologic examination revealed that the reduced neuronal density in LC, but not in other brainstem nuclei, was robustly associated with the loss of cognitive function, demonstrating that neural reserve is represented by noradrenergic innervation. Moreover, the loss of LC neurons is very much linked to reactive astrogliosis, which is regulated by noradrenaline (NA) [12].
Aerobic glycolysis in the central nervous system resides in astrocytes
In normal ageing LC neurons are reduced in number up to 25% of those neurons, responsible for ~70% of brain NA levels, are being lost in the elderly (>90 years age) [13]. Several possibilities exist to reverse the consequences of deficient noradrenergic transmission during neurodegeneration. One of these is linked to a dysfunction in glucose metabolism, also observed clinically [14]. Glucose is considered the primary source of energy in the brain, a vast energy consuming organ, consuming over one fifth of blood glucose at rest [15]. Glucose entry into the CNS from the systemic circulation takes place mainly through astrocytes [16], with their end-feet in contact with blood vessels [17]. Moreover, astrocytes are the only cell type in the brain able to synthesize glycogen, an energy reserve [18]. During the periods of increased energy demands, elicited during arousal and attention through the LC neurons, leading to enhanced neuronal activity, or under hypoglycemic conditions when normal glucose availability is insufficient for neuronal activity, stored glycogen is degraded and metabolized to L-lactate [19]. These divergent glucose pathways are part of the glycogen shunt [20]. Thus astrocytes are essential as a perpetual energy buffer for neurons and an important source of L-lactate [21], which may be transferred to fuel energy demanding neurons which lack energy reserve [22]. This transfer is known as the astrocyte-neuron lactate shuttle (ANLS) hypothesis [23] and suggests that astrocytes provide fuel to neurons.
Although both, astrocyte and neurons, metabolize glucose, evidence suggest that in astrocytes the prevailing mechanism of glucose utilization is aerobic glycolysis, also known as the Warburg effect, a characteristic of morphologically plastic and dividing cells [24]. The upregulation of aerobic glycolysis, a hallmark of the frontal cortex [25], likely involves the activation of LC neurons and release of NA [26], by activating ARs on the astroglial plasma membrane. In turn, astrocytes release L-lactate, which acts not only as energy substrate, but also as a signal and triggers elevated firing, i.e. discharge of action potentials in LC neurons [27]. Such communication may likely exist also between LC axon termini and nearby astroglia, since transcranial direct current stimulation also evokes NA-dependent activation of astroglia [28]. When the levels of NA are reduced, the NA-mediated astroglial excitation [10] which includes L-lactate induced cAMP-signaling and autocrine production of L-lactate via a yet unidentified L-lactate receptor, is reduced [29]. Decreased astrocytic aerobic glycolysis can thus lead to AD-related impairments [30] and severity of AD was recently correlated to levels of decreased rates of glycolysis [31]. Astrogliabased strategies to slow-down neurodegeneration were discussed recently and include (i) exposing the subjects and animals to enriched sensory environment or to electrical stimulation; (ii) transplanting noradrenergic neurons/ into the brain; and (iii) applying drugs that elevate NA and or act in a similar manner as agonists of ARs on astroglia, although via different receptors [10]. The latter approach targets aerobic glycolysis.
Targeting astroglial aerobic glycolysis in AD
In astrocytes the level of glycogen is modulated; adenosine, noradrenaline and serotonin induce glycogenolysis [21], while insulin and the insulin-like growth factor (IGF1), increase the glycogen content [32-34]. Insulin and IGF1 decrease cytosolic levels of free glucose in astrocytes [34], consistent with the insulin-induced glycogen build-up. Whether insulin increases glucose uptake in astrocytes is controversial. It was reported that insulin regulates glucose uptake by activating the astrocytic glucose transporters [35,36], while insulin might suppress the endogenous glucose production - similarly as in hepatocytes [37]; by the inhibition of glucose-6-phosphatase (G6Pase), present in astrocytes [38,39], which inhibits glucose uptake. Astrocytic G6Pase ensures the removal of glucose-6-phosphate (G6P) from the cytosol, thereby preventing the inhibition of hexokinase (HK) and enabling further glucose uptake [39].
Reduced levels of insulin and insulin-like growth factor 1 (IGF1) have been reported in AD brains [40] and authors proposed at the time the term “Type 3 Diabetes”, reflecting this as a pathogenic mechanism of neurodegeneration. Interestingly, in glycogen synthase knockout mice it was shown that glycogen is necessary also for associative learning [41].
The results of the Baltimore Longitudinal Study of Aging revealed that the severity of both senile plaques and neurofibrillary pathology is correlated to lower rates of glycolysis and to higher concentrations of brain tissue glucose [31]. Impaired glycolysis was characterized by the expression of key glycolytic enzymes, HK, phosphofructokinase and pyruvate kinase, which were gradually reduced from healthy to symptomatically ill AD patients.
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