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Evidence for oxidative stress in tissue samples
obtained post-mortem from brains of Alzheimer's
disease [AD] patients has been available already
ten years ago, although not as clearly as in the
new studies. In 1989, Wagner et al [1] reported a
seven-fold mean reduction in the levels of active
protease nexin-1 [PN-1], a thrombin-specific
serine proteinase inhibitor, in hippocampus tissue
samples from AD patients [1]. This brain region
shows marked neuropathology in AD, and
participates in short-term memory processing,
which is distinctly affected in the disease. In
the same study, similar PN-1 mRNA levels were
detected in tissue samples from AD patients and
controls. This implied that the reduced PN-1
activity reflected increased turnover, or
inactivation, of the protein. Indeed, PN-1 was
shown to be extremely sensitive to inactivation by
xanthine oxidase-derived oxygen free radicals [2],
the source for oxidative stress in AD brain
tissue. Together, this suggests that PN-1 is being
inactivated in-vivo in AD patients brain tissues.
Thrombin interferes with neurite outgrowth
[3] and reduces neuronal survival under stress
conditions, while its inhibitor PN-1 may prevent
neuronal cell death [4,5]. Such observations
indicate that excess proteolytic activity,
secondary to oxidative stress, may participate in
neurodegenerative processes in AD, following
oxidative inactivation of proteinase inhibitors
such as PN-1. Protection of PN-1 [and other
proteinase inhibitors] from oxidative stress
could, in part, explain the beneficial effect of
the anti-oxidants vitamin E and melatonin in AD
patients [6,7], and could be a possible target for
future therapeutic AD drugs.
References
[1] Wagner SL, Geddes JW, Cotman CW, Lau AL,
Gurwitz D, Isackson PJ, Cunningham DD.
Protease nexin-1, an antithrombin with neurite
outgrowth activity, is reduced in Alzheimer
disease.
Proc Natl Acad Sci U S A 1989;86:8284-8288
[2] Bolkenius FN, Monard D
Inactivation of protease nexin-1 by xanthine
oxidase-derived free radicals.
Neurochem Int 1995;26:587-592
[3] Gurwitz D, Cunningham DD
Thrombin modulates and reverses neuroblastoma
neurite outgrowth.
Proc Natl Acad Sci U S A 1988;85:3440-3444
[4] Smith-Swintosky VL, Zimmer S, Fenton JW 2nd,
Mattson MP
Protease nexin-1 and thrombin modulate neuronal
Ca2+ homeostasis and sensitivity to glucose
deprivation-induced injury.
J Neurosci 1995;15:5840-5850
[5] Turgeon VL, Lloyd ED, Wang S, Festoff BW,
Houenou LJ
Thrombin perturbs neurite outgrowth and induces
apoptotic cell death in enriched chick spinal
motoneuron cultures through caspase activation.
J Neurosci 1998;18:6882-6891
[6] Pitchumoni SS, Doraiswamy PM
Current status of antioxidant therapy for
Alzheimer's Disease.
J Am Geriatr Soc 1998;46:1566-1572
[7] Brusco LI, Marquez M, Cardinali DP
Monozygotic twins with Alzheimer's disease treated
with melatonin: Case report.
J Pineal Res 1998;25:260-263
Competing interests:
No competing interests
11 February 1999
David Gurwitz
National Laboratory for the Genetics of Israeli Populations
Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, ISRAEL
Evidence for oxidative stress in Alzheimer's disease
Evidence for oxidative stress in tissue samples
obtained post-mortem from brains of Alzheimer's
disease [AD] patients has been available already
ten years ago, although not as clearly as in the
new studies. In 1989, Wagner et al [1] reported a
seven-fold mean reduction in the levels of active
protease nexin-1 [PN-1], a thrombin-specific
serine proteinase inhibitor, in hippocampus tissue
samples from AD patients [1]. This brain region
shows marked neuropathology in AD, and
participates in short-term memory processing,
which is distinctly affected in the disease. In
the same study, similar PN-1 mRNA levels were
detected in tissue samples from AD patients and
controls. This implied that the reduced PN-1
activity reflected increased turnover, or
inactivation, of the protein. Indeed, PN-1 was
shown to be extremely sensitive to inactivation by
xanthine oxidase-derived oxygen free radicals [2],
the source for oxidative stress in AD brain
tissue. Together, this suggests that PN-1 is being
inactivated in-vivo in AD patients brain tissues.
Thrombin interferes with neurite outgrowth
[3] and reduces neuronal survival under stress
conditions, while its inhibitor PN-1 may prevent
neuronal cell death [4,5]. Such observations
indicate that excess proteolytic activity,
secondary to oxidative stress, may participate in
neurodegenerative processes in AD, following
oxidative inactivation of proteinase inhibitors
such as PN-1. Protection of PN-1 [and other
proteinase inhibitors] from oxidative stress
could, in part, explain the beneficial effect of
the anti-oxidants vitamin E and melatonin in AD
patients [6,7], and could be a possible target for
future therapeutic AD drugs.
References
[1] Wagner SL, Geddes JW, Cotman CW, Lau AL,
Gurwitz D, Isackson PJ, Cunningham DD.
Protease nexin-1, an antithrombin with neurite
outgrowth activity, is reduced in Alzheimer
disease.
Proc Natl Acad Sci U S A 1989;86:8284-8288
[2] Bolkenius FN, Monard D
Inactivation of protease nexin-1 by xanthine
oxidase-derived free radicals.
Neurochem Int 1995;26:587-592
[3] Gurwitz D, Cunningham DD
Thrombin modulates and reverses neuroblastoma
neurite outgrowth.
Proc Natl Acad Sci U S A 1988;85:3440-3444
[4] Smith-Swintosky VL, Zimmer S, Fenton JW 2nd,
Mattson MP
Protease nexin-1 and thrombin modulate neuronal
Ca2+ homeostasis and sensitivity to glucose
deprivation-induced injury.
J Neurosci 1995;15:5840-5850
[5] Turgeon VL, Lloyd ED, Wang S, Festoff BW,
Houenou LJ
Thrombin perturbs neurite outgrowth and induces
apoptotic cell death in enriched chick spinal
motoneuron cultures through caspase activation.
J Neurosci 1998;18:6882-6891
[6] Pitchumoni SS, Doraiswamy PM
Current status of antioxidant therapy for
Alzheimer's Disease.
J Am Geriatr Soc 1998;46:1566-1572
[7] Brusco LI, Marquez M, Cardinali DP
Monozygotic twins with Alzheimer's disease treated
with melatonin: Case report.
J Pineal Res 1998;25:260-263
Competing interests: No competing interests