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 Since
1976, Dr. Schipper’s research efforts have been largely
concentrated at the intersections of Neuroendocrinology, Brain
Aging, and Neurodegenerative Disease. Three papers (1980-3) provided
the earliest published evidence that chronic exposure to ovarian
estradiol promotes aging-related degenerative (neuritic and glial)
changes in the rodent hypothalamus implicated in reproductive
senescence and the development of polycystic ovaries. Over the
15 years, Dr. Schipper’s laboratory has contributed a large
body of evidence and novel theory concerning the role of heme
oxygenase-1 (HO-1) and peroxidase-positive astroglia in CNS senescence
and free radical-related neurodegenerative disorders. In broadest
terms, their ability to recapitulate pharmacologically a senescent
glial phenotype in primary culture and in intact rats has enabled
them to conduct studies which have important implications for
understanding, several critical issues in biology and medicine:
(i) the enhanced vulnerability of the senescent nervous systems
to parkinsonism and other free radical-related neurodegenerations.
(ii) The mechanisms responsible for pathologoical iron sequestration
and mitochondrial insufficiency in the brains of subjects with
Parkinson's and Alzheimer's disease. (iii) The role of neuronal-glial
interactions in the pathogenesis of aging-associated brain disorders.
(iv) The subcellular origin and significance of corpora amylacea
in the aging human brain.
In 1995, Dr. Schipper reported that
the heme-degrading enzyme, HO-1 is strongly up-regulated in neurons
and astrocytes of the hippocampus and temporal cortex of Alzheimer
(AD) subjects relative to age-matched controls. He then went
on to show, with the help of the McGill Memory Clinic (Jewish
General Hospital) that HO-1 protein levels are significantly
suppressed in the plasma and lymphocytes of patients with early
sporadic Alzheimer disease. Similarly, Schipper’s team
observed that lymphocyte HO-1 mRNA is down-regulated or chemically
unstable in Alzheimer subjects. They determined that "borderline" subjects
with mild cognitive impairment (MCI) failing to meet dementia
criteria exhibit HO-1 protein and mRNA values intermediate between
those of the Alzheimer and normal elderly subjects (2000). They
also found that HO-1 protein levels in the CSF (2000) and choroid
plexus (2003) are abnormally suppressed in AD patients relative
to normal values.
In 2001-5, Dr. Schipper’s lab discovered
and partially characterized a novel heme oxygenase-1 suppressor
(HOS) factor in the plasma of AD (and some MCI) patients. Dr.
Schipper is also investigating plasma protein oxidation and aberrant
glycosylation as potential biomarkers of sporadic AD. The advent
of an accurate and minimally-invasive biomarker of early sporadic
AD would facilitate patient and family counselling, the stratification
of sub-groups in the design of clinical drug trials and the interpretation
of treatment outcome measures.
RECENT PUBLICATIONS
(i) Primary
Sahlas DJ, Liberman A, Schipper HM. Role of heme oxygenase-1
in the biogenesis of corpora
amylacea. Biogerontology 3:223—231, 2002 MEDLINE link to this publication
Schipper HM, Small L, Wang X, Brawer JR. The role of porphyrin
sequestration in the biogenesis of iron-laden astrocytic inclusions
in primary culture. Dev Neurosci 24:169-176, 2002 MEDLINE link to this publication
Anthony SG, Schipper HM, Tavares R, Hovenesian V, Cortez SC,
Stopa EG, Johanson CE. Stress protein expression in the Alzheimer-diseased
choroid plexus. J Alzheimer’s Dis 5:171-177, 2003. MEDLINE link to this publication
Yu H-L, Chertkow HM, Bergman H, Schipper HM. Aberrant profiles
of native and oxidized glycoproteins in Alzheimer plasma. Proteomics
3: 2240-2248, 2003 [Erratum: 4: 279, 2004] MEDLINE link to this publication
Berlin D, Chong G, Chertkow H, Bergman H, Phillips NA, Schipper
HM. Evaluation of HFE (hemochromatosis) mutations as genetic
modifiers in sporadic AD and MCI. Neurobiol Aging
25: 465-474, 2004 MEDLINE link to this publication
Borten O, Liberman A, Tuchweber B, Chevalier S, Ferland G, Schipper
HM. Effects of dietary restriction and metal supplementation
on the accumulation of iron-laden glial inclusions in the aging
rat hippocampus. Biogerontology 5: 81-88, 2004 MEDLINE link to this publication
Diaz Z, Colombo M, Mann KK, *Su H, Smith KN, Bohle S, Schipper
HM, Miller WH. Trolox selectively enhances arsenic-mediated oxidative
stress and apoptosis in APL and other
malignant cell lines. Blood 105: 1237-1245, 2005 MEDLINE link to this publication
Diaz-Heredia Z, Assaraf MI, Miller WH, Schipper HM. Astroglial
cytoprotection by erythropoietin pre-conditioning: Implications
for ischemic and degenerative CNS disorders. J Neurochem 93:
392-402, 2005
(ii) Reviews
Mawal Y, Berlin D, *Kravitz S, Schipper HM. Heme oxygenase-1
and Alzheimer disease. In Abraham NG, Alam J, Nath KA (eds):
Heme Oxygenase in Biology and Medicine, Kluwer Academic/Plenum
Publishers, New York, pp. 145-155, 2002
Miller WH, Schipper HM, Lee JS, Singer J, Waxman S. Mechanisms
of action of arsenic trioxide. Cancer Res 62: 3893-3903, 2002 MEDLINE link to this publication
Schipper HM. Glial heme oxygenase-1 in CNS injury and disease.
In: Hertz L (ed.): Non-neuronal Cells of the Nervous System:
Function and Dysfunction, Adv Molec Cell Biol, Vol. 31, Elsevier,
Amsterdam, pp. 869-882, 2004
Schipper HM. Heme oxygenase-1: Transducer of pathological brain
iron sequestration under oxidative stress. In: LeVine S, Connor
JR, Schipper HM (eds.). Redox-active Metals in Neurological Disorders.
Ann NY Acad Sci 1012: 84-93, 2004 MEDLINE link to this publication
Schipper HM. Redox Neurology: Visions of an emerging subspecialty.
In: LeVine S, Connor JR, Schipper HM (eds.). Redox-active Metals
in Neurological Disorders. Ann NY Acad Sci 1012: 342-355, 2004 MEDLINE link to this publication
Schipper HM. Brain iron deposition and the free radical-mitochondrial
theory of ageing. Ageing Res Rev 3: 265-301, 2004 MEDLINE link to this publication
Schipper HM. Heme oxygenase expression in human central nervous
system disorders. Free Rad Biol Med 37:1995-2011, 2004 MEDLINE link to this publication
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