| Volume 1, Number
3, October 1999
Pages 139-145
Rawhi A. Omar,Y-J Chyan, Anne C. Andorn, Burkhart Poeggeler,
Nickolaos K. Robakis, Miguel A. Pappolla
Increased Expression but Reduced Activity of Antioxidant Enzymes
in Alzheimer’s Disease
Abstract: A growing body of data suggests that free radicals are
involved in the pathogenesis of Alzheimer's disease (AD). Increased
expression of antioxidant enzymes, such as superoxide dismutase
(SOD), and their co-localization to senile plaques and dystrophic
neurites have established a firm association between free-radical
mediated injury and the disease neuropathology. While several
studies have confirmed these findings, there is conflicting
information regarding the activity of some of the enzymes. In the
current report, we assayed the activity of superoxide dismutase
(SOD), catalase and glutathione peroxidase (GSH-Px) from the same
areas of the tissue showing increased expression of SOD1 and SOD2
(parallel sequential slices). Nine brains with neuropathologically
confirmed AD and six neuropathologically normal, age-matched,
controls were examined. Despite marked increased expression of
SOD1 and SOD2 within senile plaques in all the cases studied, the
activities of SOD, GSH-Px and catalase were significantly lower in
AD than in control brains. The difference was most profound in the
case of catalase followed by GSH-Px and SOD. These data are in
qualitative agreement with that of several laboratories, and support
a decrease rather than an increase, in antioxidant enzyme activity.
The findings suggest two main possibilities. On one hand, the
observed reduced activity along with antigenically increased
expression may be consistent with inactivation of excess protein
that has been synthesized under conditions of high oxidative
stress. Increased protein oxidation coupled with enzyme
inactivation is a documented, aging-associated phenomenon.
Alternatively, the increased immunoreactivity may reflect a
redistribution phenomenon as the enzymes become more concentrated at
the sites of increased oxidative stress, despite an over all
reduction in their activity.
Pages 147-153
Sozos Ch. Papasozomenos and Theognosia Papasozomenos
Androgens Prevent the Heat Shock-Induced Hyperphosphorylation But
Not Dephosphorylation of tau in Female Rats. Implications for
Alzheimer's
Disease
Abstract: We have previously shown that heat shock induces rapid
dephosphorylation of tau in both female and male rats followed by
hyperphosphorylation only in female rats. We have also shown that
the heat shock-induced hyperphosphorylation of tau is
estrogen-independent in female rats and prevented by androgens in
male rats. To investigate whether androgens could prevent the
hyperphosphorylation of tau also in female rats, twenty-three 2- to
3-month-old Sprague-Dawley rats were ovariectomized and given daily
subcutaneous injections of 1 mg/250 g of testosterone propionate for
3-5 weeks. Immunoblots of SDS cerebral extracts were analysed
qualitatively using the peroxidase-antiperoxidase technique and
phosphate-dependent and -independent anti-tau antibodies, and
quantitatively using Tau-1 and 125I-labeled protein A. We have found
that while at 0 h after heat shock tau was dephosphorylated, at 3 h
and 6 h after heat shock tau was not hyperphosphorylated, as would
be the case in non-androgen-treated female rats. In addition, tau
became dephosphorylated in non-heat-shocked control rats. Because
tau is abnormally hyperphosphorylated in Alzheimer's disease, the
possibility of using combined estrogen/androgen replacement therapy
in postmenopausal women as a preventive measure against Alzheimer's
disease should be investigated.
Pages 155-167
Mark S. Kindy, Jin Yu, Jun-Tao Guo, and Hong Zhu
Apolipoprotein Serum Amyloid A in Alzheimer’s Disease
Abstract: Alzheimer’s disease is characterized by the tissue
deposition of ß-amyloid peptide (Aß) in the brain. Recent studies
have shown apoproteins (apo) in amyloid plaques and associated with
high-density lipoprotein (HDL) particles in the cerebrospinal fluid
(CSF). Western blot analysis revealed that serum amyloid A (apoSAA)
protein was present in control and AD patients at low levels
compared to apoE and apoA-I, however, AD brains showed a significant
increase over control values. Analysis of CSF-HDL from control and
AD individuals showed that apoA-I, apoE and apoSAA were on the
particle. Immunocytochemical analysis showed that SAA was detected
in senile plaques in AD tissue, but was predominantly localized to
neuritic plaques. ApoE staining of AD brain confirmed that most
plaques contained the apoprotein, similar to Aß immunoreactivity,
whereas apoA-I expressed little staining of senile plaques. No
significant differences were detected in the level of apoSAA when
compared to APOE genotype in AD samples, suggesting that
interactions with apoE were non-specific. These data imply that the
specific interactions of SAA with Aß in the neuritic plaques may
play a role in AD.
Pages 169-182
Manish K. Pant, Veeranna, Niranjana D. Amin, and Harish C. Pant
Phosphorylation Activity in the Alzheimer’s Disease and Normal
Brain is Modulated by Microtubule-Associated Protein, Tau In Vitro.
Abstract: One of the hallmarks of Alzheimer’s disease is the
presence of abundant neurofibrillary tangles (NFTs) in the brains of
affected individuals. Hyperphosphorylated tau is a major component
of paired helical filaments (PHFs) in NFTs. Tau is a neuronal
microtubule associated protein found primarily in axons. Normal tau
promotes tubulin polymerization and stabilizes microtubule (MT)
structures, whereas hyperphosphorylated tau reduces its affinity for
MTs and destabilizes MT-structures. This results in the disruption
of vital cellular processes (e.g., axonal transport) and leads to
the degeneration of affected neurons. Processes leading to the
hyperphosphorylation of tau and formation of neurofibrillary lesions
in Alzheimer’s disease (AD) brains are not understood.
Phosphorylation of a substrate molecule like tau depends upon the
equilibrium between kinase and phosphatase activities and the
availability of their substrate molecules in a given system.
Therefore, to understand the relative roles of kinase and
phosphatase activities, we studied the long-term kinetics of
phosphorylation in AD and control brain extracts in the presence and
absence of the phosphatase inhibitor okadaic acid (OA) using
histone, casein and bacterially expressed tau as exogenous
substrates. It was found that both kinase and phosphatase
activities were higher in AD compared to control brains.
Surprisingly, between 18 and 24 hours, there was a robust increase
in phosphorylation of endogenous proteins in the brain extracts only
when bacterially expressed tau was present in the phosphorylation
reaction mixture. This pattern of phosphorylation activity was
unaffected by OA. Significant differences in the phosphorylation of
tau isoforms were also seen during this period. These data suggest
that the expression and differential phosphorylation of certain tau
isoforms may be responsible for the robust increase in
phosphorylation and may plan an important role in Alzheimer’s
pathology.
Pages 183-193
James Primavera, Bing-Xun Lu, Peter J. Riskind, Maria Iulian, Suzanne
M. de la Monte
Brain Accumulation of Amyloid-ß in Non-Alzheimer Neurodegeneration
Abstract: We report an unusual case of amyotrophic lateral sclerosis (ALS)
marked by extensive cerebral amyloid-ß deposition in small and medium-size
vessels, capillaries, and perivascular plaques in the cerebral cortex,
and in most leptomeningeal vessels. Despite considerable cerebral amyloidosis,
the patient remained cognitively intact until death. For comparison
with other neurodegenerative diseases and normal aging, we assessed the
densities of amyloid-ß-immunoreactive cortical vessels and plaques in
matched frontal and temporal lobe sections from archival uncomplicated
cases of Alzheimer’s disease (N=10), Pick’s disease (PkD;
N=4), Parkinson’s disease (PD; N=6), Diffuse Lewy body disease (DLBD;
N=7), progressive supranuclear palsy (PSP; N=5), multiple systems atrophy
(MSA; N=4), ALS (N=7), or normal aging (N=10) by semi-quantitative grading
(0 to 3+). Moderate (2+) or abundant (3+) cerebrovascular
amyloid-ß immunoreactivity was detected in 8/10 AD, 3/7 DLBD, 3/6 PD,
1 each with PSP or PkD, and 2/10 controls. Moderate or abundant
densities of amyloid-ß-immunoreactive diffuse plaques were detected in
all cases of AD or DLBD, 4/6 with PD, 3/5 with PSP, and 2/10 controls.
Moderate or abundant amyloid-ß-immunoreactive mature (dense core) plaques
were present in all cases of AD or DLBD, and 3 each with PD or PSP.
Importantly, amyloid-ß-immunoreactivity was not observed in the 4 MSA
or 7 archival ALS cases. This study demonstrates that prominent
amyloid-ß accumulation in cerebral vessels and plaques occurs frequently
in AD, DLBD, PSP, and PD, but not in ALS or MSA, indicating that the case
described is unique. The lack of cognitive impairment in the case
presented argues against the idea that extensive amyloid-ß deposition
in the brain causes dementia.
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