Journal of Alzheimer's Disease - Volume 1, issue 3

Authors: Omar, Rawhi A. | Chyan, Y.-J. | Andorn, Anne C. | Poeggeler, Burkhart | Robakis, Nikolaos K. | Pappolla, Miguel A.

Article Type: Research Article

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 immuno-reactivity 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. Show more

Keywords: Alzheimer's disease, superoxide dismutase, amyloid beta protein, oxidative stress, senile plaques, Aβ, oxidation, antioxidant enzymes

DOI: 10.3233/JAD-1999-1301

Citation: Journal of Alzheimer's Disease, vol. 1, no. 3, pp. 139-145, 1999

Authors: Papasozomenos, S.C. | Papasozomenos, T.

Article Type: Research Article

Abstract: We have previously shown that heat shock induces rapid dephosphorylation of τ in both female and male rats followed by hyperphosphorylation only in female rats (J Neurochem 66 (1996), 1140–1149). We have also shown that the heat shock-induced hyperphos-phorylation of τ is estrogen-independent in female rats and prevented by androgens in male rats (Proc Natl Acad Sci USA 94 (1997), 6612–6617). To investigate whether androgens could prevent the hyperphosphorylation of τ 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-τ antibodies, and quantitatively using Tau-1 and 125 I-labeled protein A. We have found that while at 0 h after heat shock τ was dephosphorylated, at 3 h and 6 h after heat shock τ was not hyperphosphorylated, as would be the case in non-androgen-treated female rats (ref. above). In addition, τ became dephosphorylated in non-heat-shocked control rats. Because τ 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. Show more

DOI: 10.3233/JAD-1999-1302

Citation: Journal of Alzheimer's Disease, vol. 1, no. 3, pp. 147-153, 1999

Authors: Kindy, Mark S. | Yu, Jin | Guo, Jun-Tao | Zhu, Hong

Article Type: Research Article

Abstract: Alzheimer's disease is characterized by the tissue deposition of β-amyloid peptide (Aβ) 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. Immuno-cytochemical 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 Aβ 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 Aβ in the neuritic plaques may play a role in AD. Show more

Keywords: Alzheimer's disease, serum amyloid A protein, apoprotein, β-amyloid peptide, high-density lipoprotein

DOI: 10.3233/JAD-1999-1303

Citation: Journal of Alzheimer's Disease, vol. 1, no. 3, pp. 155-167, 1999

Authors: Pant, Manish K. | Veeranna, | Amin, Niranjana D. | Amin, Nivee | Pant, Harish C.

Article Type: Research Article

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 difference in the phosphorylation of tau isoforms was 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 play an important role in Alzheimer's pathology. Show more

DOI: 10.3233/JAD-1999-1304

Citation: Journal of Alzheimer's Disease, vol. 1, no. 3, pp. 169-182, 1999

Authors: Primavera, James | Lu, Bing-Xun | Riskind, Peter J. | Iulian, Maria | de la Monte, Suzanne M.

Article Type: Research Article

Abstract: We report an unusual case of amyotrophic lateral sclerosis (ALS) marked by extensive cerebral amyloid-β 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 neuro-degenerative diseases and normal aging, we assessed the densities of amyloid-β-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-β 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-β-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-β-immunoreactive mature (dense core) plaques were present in all cases of AD or DLBD, and 3 each with PD or PSP. Importantly, amyloid-β-immunoreactivity was not observed in the 4 MSA or 7 archival ALS cases. This study demonstrates that prominent amyloid-β 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-β deposition in the brain causes dementia. Show more

Keywords: Amyotrophic lateral sclerosis, amyloid-β, neurodegeneration

DOI: 10.3233/JAD-1999-1305

Citation: Journal of Alzheimer's Disease, vol. 1, no. 3, pp. 183-193, 1999

Authors: Summers, William K.

Article Type: Other

DOI: 10.3233/JAD-1999-1306

Citation: Journal of Alzheimer's Disease, vol. 1, no. 3, pp. 195-195, 1999