No abstract

Glycogen synthase kinase3 (GSK3) is emerging as a prominent drug target in the CNS. The most exciting of the possibilities of GSK3 lies within the treatment of Alzheimer's disease (AD) where abnormal increases in GSK3 levels and activity have been associated with neuronal death, paired helical filament tau formation and neurite retraction as well as a decline in cognitive performance. Abnormal activity of GSK3 is also implicated in stroke. Lithium, a widely used drug for affective disorders, inhibits GSK3 at therapeutically relevant concentrations. Thus while the rationale remains testable, pharmaceutical companies are investing in finding a selective inhibitor of GSK3. In the present review, we summarize the properties of GSK3, and discuss the potential for such a therapy in AD, and other CNS disorders.

Apoptosis can be defined as the regulated death of a cell and is conducted by conserved pathways. Apoptosis of neurons after injury or disease differs from programed cell death, in the sense that neurons in an adult brain are not "meant" to die and results in a loss of function. Thus apoptosis is an honorable process by a neuron, a cell with limited potential to replace itself, choosing instead to commit suicide to save neighboring cells from release of cellular components that cause injury directly or trigger secondary injury resulting from inflammatory reactions. The excess of apoptosis of neuronal cells underlies the progressive loss of neuronal populations in neurodegenerative disorders and thus is harmful. Mitochondria are the primary source for energy in neurons but are also poised, through the "mitochondrial apoptosis pathway," to signal the demise of cells. This duplicity of mitochondria is discussed, with particular attention given to the specialized case of pathological neuronal cell death.

An extensive characterization of fetal mouse brain cell aggregates has been performed using immunohistochemical and stereological methods. Single cell suspensions from mechanically dissociated cortex and hippocampus were cultured in serum-free, B27-supplemented medium under constant gyratory agitation for up to 56 days. Three-dimensional aggregates started to form immediately after seeding and reached a final average size of 500 microm in diameter. Among the cell types identified, neurons were the most abundant cells in the aggregates, followed by astrocytes, microglia, and oligodendrocytes. Western blotting for synaptophysin and immunostaining for neurotransmitter-related molecules indicated the presence of well-defined phenotypic characteristics of the neurons in this culture system, suggesting functionality. Proliferating cells, many with neural precursor cell properties, were seen throughout the culture period and could be isolated from the aggregates even after 2 months in culture. Neural precursor cells were isolated from the aggregates after more than 1 month in culture; these cells were successfully differentiated into neurons, astrocytes, and oligodendrocytes. The aggregate culture system may provide a versatile tool for molecular dissection of processes identified in mouse models, including transgenic animals and manipulation of neural precursor cells.

Genetics and pathology have proven to be an effective combination to identify an evolving and deepening landscape of pathways and potential therapeutic targets in neurodegenerative diseases. Initially this landscape appeared to be populated with distinct therapeutic targets but with potentially overlapping mechanisms in each neurodegenerative disease. Our understanding has expanded to recognize that multiple pathologies are common in neurodegenerative disease, and that there is considerable overlap in pathways and targets driving neurodegenerative diseases. This potentially opens the way for future treatments to be indicated by tissue pathology and genetic basis rather than clinical phenotype. The potential to treat neurodegenerative disease by addressing underlying pathophysiology is still in the early days and challenges remain, especially the likely need to address pathologies early in disease. This will require redefinition of diagnosis and the tools to enable earlier diagnosis.