Does apoptosis have a role in neurodegeneration?

Cells within the central nervous system die during both acute and chronic
neurodegenerative disorders.

Since the morphological and biochemical features of apoptosis were first
described, neuroscientists have been asking whether this cell death is due
to apoptosis and whether elucidating the mechanisms of apoptosis can
provide new treatment strategies for intractable diseases such as stroke,
Alzheimer's disease, and Huntington's disease.

Detecting apoptosis

Much debate has ensued.

Firstly, cell death in the central nervous system may not fit perfectly
with our current classification of apoptosis and necrosis, which was
defined using peripheral cells.

Some of the methods used may not distinguish conclusively between apoptosis
and necrosis.

For example, transferase-mediated dUTP nick end labelling (TUNEL), a
staining method that detects the broken ends of DNA within cells, is used
to provide evidence of apoptosis. However, DNA can be fragmented in
necrosis too.

Secondly, clinical symptoms may result from loss of neuronal function
rather than apoptotic cell death.

Many chronic neurodegenerative diseases are associated with intracellular
aggregates of mutated proteins that cannot readily be disrupted, even by
aggressive laboratory procedures.

Such deposits may compromise neuronal function[---]for example, by blocking
transport of nutrients along axons.

A study of Huntington's disease in mice has shown that if generation of the
mutant protein is halted, the aggregates are dissolved by the proteasome
(the cellular machinery for removing unwanted proteins) and the
neurological scores of the mice improve.[1]

This suggests that, initially at least, symptoms may result from
compromised neuronal function, with cell death having a subsequent role.

Supporting evidence

Evidence supporting a role for apoptosis in neurodegenerative diseases has
come from studying rodent brain cells and by manipulation in animal models
of the levels of expression or activity of key molecules involved in
apoptosis.

Active caspases, the proteases activated during apoptosis, have been
detected in dying neurones taken from patients with Alzheimer's disease.

These enzymes can cleave [beta ]-amyloid, a protein implicated in the
pathogenesis of Alzheimer's, generating a pro-apoptotic protein.[2]

Furthermore, [beta ]-amyloid can induce apoptosis in cultured neurones,[3]
but cells lacking caspases become resistant to [beta ]-amyloid.

Similarly, although normal huntingtin, which when mutated caused
Huntington's disease, is required for survival of neurones, mutant
huntingtin can induce apoptosis of neurones.[4]

Huntingtin can also be cleaved by caspases, and cleavage is enhanced by
mutation of the protein.[5]
Preventing cleavage by caspases reduces the toxicity of the mutant
huntingtin.

Such studies provide circumstantial evidence that apoptosis participates in
chronic neurodegeneration.

Some of the best evidence for the role of apoptosis in neurodegeneration
comes from studies of brain ischaemia or stroke (figure).

Although necrosis predominates in the severely ischaemic core of injured
tissue, apoptosis occurs in the less ischaemic region that surrounds the
core.[6]

Up regulation of several proteins that participate in apoptosis (for
example, caspase-3) has been detected in stroke damaged brain tissue, and
animals that have been engineered to overexpress anti-apoptotic proteins or
that have been treated with caspase inhibitors show less damaged tissue
after experimentally induced stroke.

The evidence therefore suggests that apoptosis has a role in
neurodegeneration, and the studies described above highlight the
possibility that pro-apoptotic agents such as caspases might be new targets
for therapeutic intervention.

Caspase inhibitors would seem especially applicable to situations of acute
degeneration such as stroke.

It remains to be seen whether they can also be used for slowly progressing
chronic neurodegenerative conditions, where neuronal function may fail
before cell death removes the damaged neurone.

Footnotes

Funding: RG is supported by the Wellcome Trust.

Competing interests: None declared.

References

1.  Yamamoto A, Lucas JJ, Hen R. Reversal of neuropathology and motor
dysfunction in a conditional model of Huntington's disease. Cell 2000; 101:
57-66[Medline].
2.  Gervais FG, Xu D, Robertson GS, Vaillancourt JP, Zhu Y, Huang JQ, et
al. Involvement of caspases in proteolytic cleavage of Alzheimer's
amyloid-ß precursor protein and amyloidogenic Aß peptide formation. Cell
1999; 97: 395-406[Medline].
3.  Barinaga M. Is apoptosis key in Alzheimer's disease? Science 1998; 281:
1303-1304[Full Text].
4.  Cattaneo E, Rigamonti D, Goffredo D, Zuccato C, Squitieri F, Sipione S.
Loss of normal huntingtin function: new developments in Huntington's
disease research. Trends Neurosci 2001; 24: 182-188[Medline].
5.  Goldberg YP, Nicholson DW, Rasper DM, Kalchman MA, Koide HB, Graham RK,
et al. Cleavage of huntingtin by apopain, a proapoptotic cysteine protease,
is modulated by the polyglutamine tract. Nature Genet 1996; 13:
442-449[Medline].
6.  Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke:
an integrated view. Trends Neurosci 1999; 22: 391-397[Medline].


Rosemary M Gibson, research fellow.
School of Biological Sciences, University of Manchester, Manchester M13 9PT
BMJ 2001;322:1539-1540 ( 23 June )
http://bmj.com/cgi/content/full/322/7301/1539?lookupType=volpage&vol=322&fp=
1539&view=short

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