Neurodegenerative diseases represent a major challenge for today’s society in terms of the large and rapidly increasing number of the people that are afflicted and the general lack of effective treatments. Neurodegeneration is the progressive loss of neuron structure or neuron function, including death of neurons. The term acute neurodegeneration describes clinical conditions in which neurons are rapidly damaged and usually die in response to a sudden insult. This description encompasses stroke, head injury, cerebral or subarachnoid haemorrhage, and ischaemic brain damage derived from fetal or perinatal hypoxia.
Many late-onset neurodegenerative diseases are caused by aggregateprone proteins1 . These diseases, known as proteinopathies, include conditions in which the proteins are predominantly cytosolic (such as Parkinson’s disease, PD, and adult-onset Huntington’s disease, HD), predominantly intranuclear (for example, spinocerebellar ataxia type 1), aggregated in the endoplasmic reticulum (as seen with neuroserpin mutations that cause familial encephalopathy with neuroserpin inclusion bodies) and secreted extracellularly (for example, amyloid-β in Alzheimer’s disease). The capacity to aggregate (although not necessarily the aggregates themselves) is correlated with toxicity. For instance, the point mutations in α-synuclein and tau that cause dominant forms of PD and frontotemporal dementia, respectively, aggregate more rapidly than the wildtype proteins. The same phenomenon is seen with the polyglutamine expansion mutations that cause diseases such as HD — in these diseases earlier onset correlates with longer polyglutamine tracts, and aggregation propensity increases with polyglutamine tract length.
Inflammatory processes have been implicated in both acute and chronic neurodegenerative conditions. The CNS differs in its inflammatory response to other tissues. In general terms, cellular infiltration in the brain in response to inflammation, infection and injury is weaker and delayed, yet many inflammatory responses can be induced rapidly. These include the activation of microglia, and the expression and release of classical inflammatory mediators, such as acute-phase proteins, eicosanoids, complement and cytokines. Cytokines have been implicated as mediators and inhibitors of diverse forms of neurodegeneration. They are induced in response to brain injury and have diverse actions that can cause, exacerbate, mediate and/or inhibit cellular injury and repair.