The contribution of cell death to pathological conditions is reflected in the mammalian adult nervous system. Here, degeneration can be evoked either by acute necrotic insults like stroke, trauma and ischemia, or occurs as a component of neurodegenerative disorders.
Neurodegenerative insults; ischemia and excitotoxicitv
In ischemia, blood flow to tissues is interrupted, leading to tissue anoxia. Ischemia occurs during cardiac arrest (complete global brain ischemia) and in ischemic stroke (regional incomplete brain ischemia). Several lethal pathways ensue after an ischemic insult. As a direct consequence, ATP stores are depleted, thereby triggering membrane depolarization. Membrane depolarization activates voltage-gated calcium channels (VGCC) and phospholipase C (PLC) and the release of the excitatory neurotransmitter glutamate. Excessive glutamate signaling overstimulates glutamateresponsive NMDA-receptors and AMPA-receptors and leads to an increase of intracellular Ca2+ concentration. This situation, called excitotoxicity, is a hallmark of necrotic neurodegeneration. NMDA-receptors gate Ca2+, and activation of AMPA-receptors induces Na+ influx, which can trigger the reverse action of Na+-Ca2+ exchangers and therefore add to Ca2+ overload. The non-physiologically high [Ca2+]i (achieved by excitotoxicity and VGCC activity) activates phospholipases, calpains and calcineurin. These molecules in concert ensure cellular disruption. Lipid peroxidation is a deleterious consequence of PLC and PLA2 activity, mediated by lipolysis, including the release of free arachidonic acid. Calpains are suggested to play a role in excitotoxicity, ischemia, as well as in Alzheimer’s disease, where they down-regulate protein synthesis by translation-initiation factor proteolysis, cleave other cellular substrates such as spectrin and fodrin, and possibly trigger caspase activity. Calcineurin can activate NOS (nitric oxide synthase) and induce lipid peroxidation leading to further membrane damage. An additional consequence of ischemia-induced intracellular Ca2+ increase is the depletion of ER Ca2+ stores, consequently triggering ER stress.
The ultrastructure of excitotoxic degeneration reveals characteristics of necrotic cell death: swelling of organelles, loss of electron density of the cytoplasm, swelling of the cell and rupture of the plasma membrane. However, observations in excitotoxicity also challenge the classic categorization of cell death as either apoptotic or necrotic. In some cases of excitotoxicity, both apoptosis and necrosis are induced in parallel, seen as a mixture of morphological markers for both forms of cell death in the same tissue or culture cell (DNA-laddering, condensation of nucleus and cytoplasm, chromatin clumping, membrane rupture, etc.). This led to the suggestion of the 'apoptosis- necrosis-continuum' model where typical necrotic and apoptotic characteristics can coexist. It is thought that the severity of the insult and the maturity of the affected neurons, as well as biochemical parameters (such as pH-value, ATP-supply and ion concentration) can greatly influence the mode of cell death, i.e. whether necrosis or apoptosis is promoted by a given insult or a hybrid of both forms occurs.
Cell death in neurodegenerative diseases
Several neurodegenerative disorders have been associated with mutations in specific genes, e.g. presenilin 1 and 2, and amyloid precursor protein (APP) in Alzheimer's disease (AD), α-synuclein, parkin, UCH-L1 and DJ-1 in Parkinson’s disease (PD), Huntingtin in Huntington’s disease, and alsin and SOD1 in Amyotrophic lateral sclerosis (ALS). Most of these diseases are characterized by neuronal inclusions made of abnormal aggregates of wild type protein, or by extracellular deposits or intracellular inclusions made from mutant and/or misfolded proteins (Lewy bodies made from α-synuclein, amyloid deposits, huntingtin-aggregates, etc.), which are linked to improper function and death of the neurons. Based on the appearance of these non-native protein conformations, Alzheimer’s disease, Parkinson’s disease, amyloidosis, Huntington’s disease, prion encephalopathies etc., are classified as conformational diseases.
Apoptosis appears to contribute to neurodegenerative diseases. Evidence for participation of apoptotic cell death include positive TUNEL staining (a method to detect DNA laddering, as a hallmark of apoptosis), activated caspases, and increased ex