Towards a new understanding of NCL pathogenesis.

The Neuronal Ceroid Lipofuscinoses (NCLs, Batten disease) are a group of inherited neurodegenerative disorders that have been traditionally grouped together on the basis of certain shared clinical and pathological features. However, as the number of genes that appear to cause new forms of NCL continues to grow, it is timely to reassess our understanding of the pathogenesis of these disorders and what groups them together. The various NCL subtypes do indeed share features of a build-up of autofluorescent storage material, progressive neuron loss and activation of the innate immune system. The characterisation of animal models has highlighted the selective nature of neuron loss and its intimate relationship with glial activation, rather than the generalised build-up of storage material. More recent data provide evidence for the pathway-dependent nature of pathology, the contribution of glial dysfunction, and the involvement of new brain regions previously thought to be unaffected, and it is becoming apparent that pathology extends beyond the brain. These data have important implications, not just for therapy, but also for our understanding of these disorders. However, looking beneath these broadly similar pathological themes evidence emerges for marked differences in the nature and extent of these events in different forms of NCL. Indeed, given the widely different nature of the mutated gene products it is perhaps more surprising that these disorders resemble each other as much as they do. Such data raise the question whether we should rethink the collective grouping of these gene deficiencies together, or whether it would be better to consider them as separate entities. This article is part of a Special Issue entitled: Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease).

Amyloid ß 1-42 induces hypometabolism in human stem cell-derived neuron and astrocyte networks.

Alzheimer's disease (AD) is the most common form of dementia, affecting more than 35 million people worldwide. Brain hypometabolism is a major feature of AD, appearing decades before cognitive decline and pathologic lesions. To date, the majority of studies on hypometabolism in AD have used transgenic animal models or imaging studies of the human brain. As it is almost impossible to validate these findings using human tissue, alternative models are required. In this study, we show that human stem cell-derived neuron and astrocyte cultures treated with oligomers of amyloid beta 1-42 (Aß1-42) also display a clear hypometabolism, particularly with regard to utilization of substrates such as glucose, pyruvate, lactate, and glutamate. In addition, a significant increase in the glycogen content of cells was also observed. These changes were accompanied by changes in NAD(+)/NADH, ATP, and glutathione levels, suggesting a disruption in the energy-redox axis within these cultures. The high energy demands associated with neuronal functions such as memory formation and protection from oxidative stress put these cells at particular risk from Aß-induced hypometabolism. Further research using this model may elucidate the mechanisms associated with Aß-induced hypometabolism.

Functional astrocyte-neuron lactate shuttle in a human stem cell-derived neuronal network.

The NT2.D1 cell line is one of the most well-documented embryocarcinoma cell lines, and can be differentiated into neurons and astrocytes. Great focus has also been placed on defining the electrophysiological properties of the neuronal cells, and more recently we have investigated the functional properties of their associated astrocytes. We now show for the first time that human stem cell-derived astrocytes produce glycogen and that co-cultures of these cells demonstrate a functional astrocyte-neuron lactate shuttle (ANLS). The ANLS hypothesis proposes that during neuronal activity, glutamate released into the synaptic cleft is taken up by astrocytes and triggers glucose uptake, which is converted into lactate and released via monocarboxylate transporters for neuronal use. Using mixed cultures of NT2-derived neurons and astrocytes, we have shown that these cells modulate their glucose uptake in response to glutamate. Additionally, we demonstrate that in response to increased neuronal activity and under hypoglycaemic conditions, co-cultures modulate glycogen turnover and increase lactate production. Similar results were also shown after treatment with glutamate, potassium, isoproterenol, and dbcAMP. Together, these results demonstrate for the first time a functional ANLS in a human stem cell-derived co-culture.