neuronal death

Types

 developmental neuronal death
 ischemia-induced neuronal death

In Alzheimer disease

Apoptosis is a form of programmed cell death that involves changes in the cytoplasm, ER, mitochondria and nucleus.

It typically includes the production and/or activation of proteins such as Bax and Bad that increase the permeability of mitochondrial and ER membranes resulting in the release into the cytoplasm of cytochrome c from the mitochondria and calcium from the ER.

The latter events then activate enzymes called caspases that cleave various protein substrates to sculpt morphological and biochemical aspects of the cell death process.

For example, cleavage of cytoskeletal proteins and ion channel proteins causes cell shrinkage and may prevent necrosis, whereas cleavage of DNA degrades chromosomes. Evidence that many neurons undergo apoptosis in AD includes the presence of high levels of activated apoptotic proteins such as caspase-3 and Bax in neurons that exhibit neurofibrillary tangle pathology.

In addition, DNA damage and upregulation of the pro-apoptotic proteins p53 and Bax occur in vulnerable neuronal populations at a relatively early stage in the disease process.

Familial AD (FAD) mutations in presenilins render neurons vulnerable to apoptosis induced by A, trophic factor deprivation and other stimuli93, consistent with an apoptotic mode of neuronal death in patients with these presenilin mutations.

APP mutations are also sufficient to trigger apoptosis in cultured cells.

The triggers of cell death in AD may include A, activation of glutamate receptors, increased oxidative stress, DNA damage and elevation of intracellular calcium levels.

Once triggered, apoptosis proceeds with the production and/or activation of proteins such as p53, Bax, Bad and Par-4 that induce mitochondrial membrane permeability changes.

Release of cytochrome c and AIF (apoptosis-inducing factor) from mitochondria and release of calcium from the ER occurs, followed by activation of the apoptosome, a protein complex that includes cytochrome c, Apaf-1 and caspase-9 (CASP9) and caspase-3 (CASP3) .

Finally, cleavage of various substrate proteins by caspases and endonucleases occurs. Neurotoxic forms of A may be a trigger of apoptosis in AD because pro-apoptotic proteins are associated with A deposits in the brains of AD patients and A can induce apoptosis of cultured neurons.

Exposure of neurons to A induces an apoptotic cascade that involves: upregulation of p53, Bax and Par-4; mitochondrial membrane permeability transition and release of cytochrome c; activation of the apoptosome resulting in caspase-3 activation; and nuclear chromatin fragmentation.

Neurons treated with inhibitors of p53, agents that stabilize mitochondrial and ER membranes or caspase inhibitors are resistant to being killed by A93, 94. In addition to A, C-terminal proteolytic products of APP have been implicated in neuronal apoptosis.

In addition to mitochondrial alterations, abnormalities in the ER and nucleus have been documented in studies of AD patient tissue and cell culture and animal models.

FAD PS1 mutations have been shown to render neurons vulnerable to apoptosis, apparently by altering ER stress responses and ER calcium regulation.

Apoptosis in AD may involve DNA-damage-response pathways and inappropriate activation of cell cycle pathways involving the cyclin-dependent kinase 5 and its neuron-specific activator p35.

As evidence, proteolytic cleavage of p35 produces p25, which accumulates in the brains of AD patients and in cultured neurons exposed to A1-42, and A-induced neuronal death is mediated by the ATM-dependent DNA-damage-response pathway.

Increasing evidence suggests that ubiquitin-proteasomal degradation of proteins is impaired in AD, resulting in the abnormal accumulation of damaged proteins in neurons (UBB + 1 mutations).

In this regard it was recently reported that a ubiquitin-conjugating enzyme called E2-25K/Hip-2 mediates A-induced inihibition of proteasome activity, which is required for A-induced apoptosis.

There are several mechanisms that can protect neurons against apoptosis, including activation of cell surface receptors coupled to anti-apoptotic pathways, such as those activated by neurotrophic factors and sAPP, and agonists that activate the cyclic AMP second messenger pathway.

References

 Shen Y, He P, Zhong Z, McAllister C, Lindholm K. Distinct destructive signal pathways of neuronal death in Alzheimer’s disease. Trends Mol Med. 2006 Dec;12(12):574-9. PMID: 17055782

 Hou ST, McManus JP: Molecular mechanisms of cerebral ischemia-induced neuronal death. Int Rev Cytol 221:93, 2002.

 Johnson EM Jr, Deckwerth TL. Molecular mechanisms of developmental neuronal death. Annu Rev Neurosci. 1993;16:31-46. PMID: 8460896