Giulio Maria Pasinetti

Regional distribution of cyclooxygenase-2 in the hippocampal formation in Alzheimer's disease

Cyclooxygenase‐2 (COX‐2), a key enzyme in prostanoid biosynthesis, may represent an important therapeutic target in Alzheimers disease (AD). In the present study, we explored the regulation of COX‐2 in the hippocampal formation in sporadic AD. Using semiquantitative immunocytochemical techniques, we found that in AD cases (vs. age‐matched controls) neurons of the CA1–CA4 subdivisions of the hippocampal pyramidal layer showed elevation of COX‐2 signal; COX‐2 levels correlated with amyloid plaque density. In contrast, the level of COX‐2 immunostaining in the dentate gyrus granule neurons was not elevated in AD. No expression of COX‐2 in cells with glial morphology was found in any case examined. In parallel, in vitro studies found that neurons derived from transgenic mice with neuronal overexpression of COX‐2 are more susceptible to β‐amyloid (Aβ) toxicity, with potentiation of redox impairment. The results indicate elevated expression of neuronal COX‐2 in subregions of the hippocampal formation in AD and that such elevation may potentiate Aβ‐mediated oxidative stress. J. Neurosci. Res. 57:295–303, 1999.

Cyclooxygenase and inflammation in Alzheimer's disease: experimental approaches and clinical interventions.

Many epidemiological studies suggest that use of non‐steroidal anti‐inflammatory drugs (NSAIDs) delay or slow the clinical expression of Alzheimers disease (AD). While it has been demonstrated that neurodegeneration in AD is accompanied by specific inflammatory mechanisms, including activation of the complement cascade and the accumulation and activation of microglia, the mechanism by which NSAIDs might affect these or other pathophysiological processes relevant to AD has been unclear. New evidence that cyclooxygenase (COX) is involved in neurodegeneration along with the development of selective COX inhibitors has led to renewed interest in the therapeutic potential of NSAIDs in AD. J. Neurosci. Res. 54:1–6, 1998.

Inflammatory mechanisms in neurodegeneration and Alzheimer's disease: The role of the complement system

This review discusses key findings indicating potential roles of the complement (C)-system in chronic inflammation in Alzheimers disease (AD) brain. Although there is no means to cure or prevent the disease, recent studies suggest that antiinflammatory drugs may delay the onset of AD dementia. One target of these drugs may be the (C)-system, which is best known for its roles in inflammatory processes in peripheral tissues. However, recent data show C-system expression and regulation in brain cells, and C-system protein deposition in AD plaques. It is still nuclear whether C-system activation contributes to neuropathology in the AD brain, as shown in multiple sclerosis (MS). New clinical studies with antiinflammatory agents are now under general consideration by the Alzheimers Disease Cooperative Study program. In this review I outline research directions which address possible C-system contributions to neurodegeneration. Finally, I discuss potential pharmacological interventions designed to control segments of classical inflammatory cascades in which the C-system is highly implicated. These aspects are critical to the understanding of C-mediated responses in normal and pathologic brain.

Cyclooxygenase and Alzheimer's disease: implications for preventive initiatives to slow the progression of clinical dementia

Industry and academia are devoting a tremendous amount of resources to the testing of anti-inflammatory drugs for the treatment of Alzheimers disease (AD). This trend is the result of the growing consensus supporting the inflammatory hypothesis of AD. If anti-inflammatory strategies succeed in slowing the rate of disease progression, the impact on patients and families could be enormous. However, given the large number of candidates in the pool of anti-inflammatory drugs and given their widely divergent activities, it is essential to use methods which optimizes drug selection and study design. Pilot studies of anti-inflammatory regimens are useful in determining tolerability. However, these studies have limited value in estimating effective size since disease-modification, rather than symptomatic improvement, is the ultimate goal. Better understanding of the influence of inflammatory activity and the specific mechanisms which play an early role in the progression of the disease, will improve the likelihood of successfully identifying an effective anti-inflammatory treatment strategy. This review outlines directions in research that address possible contributions of cyclooxygenase (COX)-2, COX-1 and other inflammatory mediators to AD neurodegeneration. Finally, this article addresses potential interventions designed to control segments of classical inflammatory cascades in the brain in which cyclooxygenase is highly implicated. These considerations are critical to understand the role of cyclooxygenase in the clinical progression of AD.

Glucocorticoids in Alzheimer’s Disease

SummaryThe inflammatory hypothesis of Alzheimer’s disease states that specific inflammatory mechanisms, including the cytokine-driven acute-phase response, complement activation and microglial activation, contribute to neurodegeneration. If the hypothesis is correct, anti-inflammatory treatment aimed at suppression of these mechanisms could slow the rate of disease progression. Towards this goal, a multicentre trial of prednisone in Alzheimer’s disease is under way and pilot studies of other anti-inflammatory regimens are being conducted.

Expression profile of genes associated with antimetastatic gene: nm23-Mediated metastasis inhibition in breast carcinoma cells

Metastases of various malignancies have been shown to be inversely related to the abundance of nm23 protein expression. However, the downstream pathways involved in nm23‐mediated suppression of metastasis have not been elucidated. In the present investigation, we used cDNA microarrays to identify novel genes and functional pathways in nm23‐mediated spontaneous breast metastasis. Microarray experiments were performed in a pair of cell lines, namely, C‐100 (only vector transfected; highly metastatic) and H1‐177 (nm23 transfected; low metastatic), derived from human mammary carcinoma cell line MDA‐MB‐435. The cDNA microarray analysis using GeneSpring software revealed significant as well as consistent alterations in the expression (up‐ and downregulation) of 2,158 genes in a total of 18,889 genes between high and low metastatic cells. Some of these genes were grouped into 6 functional categories, namely, invasion and metastasis, apoptosis and senescence, signal transduction molecules and transcription factors, cell cycle and repair, adhesion, and angiogenesis to extrapolate an association between these genes and different functional pathways involved in nm23‐regulated metastasis. The results suggest that nm23 gene plays a major role in metastasis and its mechanism of action of metastasis suppression may involve downregulation of genes associated with cell adhesion, motility (integrins α2, ‐8, ‐9, ‐L and ‐V, collagen type VIII α1, fibronectin 1, catenin, TGF‐β2, FGF7, MMP14 and 16, ErbB2) and possibly certain tumor/metastasis suppressors (2 members of SWI/SNF‐related matrix‐associated proteins 2 and 5 and PTEN).

HLA-DR4 influences glial activity in Alzheimer's disease hippocampus

The importance of inflammatory/immune mechanisms in Alzheimers disease is supported by evidence that the human leukocyte antigen (HLA)-DR genotype influences risk of the disease, with a protective effect associated with the HLA-DR4 allele. We investigated the influence of the HLA-DR4 allele on glial activity, assessed by quantification of glial fibrillary acidic protein (GFAP), in hippocampal tissue from subjects with Alzheimers disease. The mean GFAP level was significantly higher in Alzheimers disease hippocampal specimens lacking the HLA-DR4 allele compared to specimens with similar neuropathological findings that were HLA-DR4 positive. Apolipoprotein E genotype had no influence on GFAP levels. These results indicate that HLA-DR4 may exert a protective influence on Alzheimers disease via modulation of glial activity.

Cyclooxygenase as a target for the antiamyloidogenic activities of nonsteroidal anti-inflammatory drugs in Alzheimer's disease.

A large number of epidemiological studies have addressed the possible protective effect of anti-inflammatory drug use with regard to Alzheimer’s disease (AD). The most convincing of these studies – the Baltimore Longitudinal Study of Aging – utilized data collected prospectively, thereby minimizing recall bias issues. However, despite this evidence, therapeutic studies investigating nonsteroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase-1 (COX-1) and COX-2 inhibitors and steroids, do not support this hypothesis. This discrepancy may be due to the fact that the bulk of epidemiological evidence has examined the likely incidence of AD prior to the onset of clinical symptoms of disease. On the basis of this information, the article will attempt to formulate a possible scenario, in which optimal NSAIDs might be tested in the most favorable clinical therapeutic conditions in order to determine whether NSAIDs can provide beneficial treatment for the clinical progression of AD dementia.

Fractionation of Grape Seed Proanthocyanidins for Bioactivity Assessment

Grape seed extract (GSE) is rich in flavonoids, particularly proanthocyanidins (PAs). PAs and their monomers are strong antioxidants and have been ascribed a number of potential activities beneficial to health, including protection against cancers, cardiovascular disease, and Alzheimer’s disease. However, little is known about the chemical nature and the concentration of bioactive polyphenols to which the body is exposed after ingestion of GSE. This chapter summarizes recent advances in fractionation techniques for PAs, including work from our laboratory on fractionation of GSE in quantities sufficient for analysis of its protective effects in whole animal models of Alzheimer’s disease. Several techniques, ranging from fractionation using liquid–liquid extraction to separation on Toyopearl resin and normal-phase HPLC, have been optimized to separate and purify monomeric, oligomeric, and polymeric PAs from GSE. The extraction and separation efficiencies of the various techniques are discussed.

33 – Anti-inflammatory and Antioxidant Therapies in Alzheimer's Disease

Inflammatory mechanisms and oxidative stress usually contribute to neurodegeneration in Alzheimers disease (AD) and outline the current efforts to develop anti-inflammatory and anti-oxidant treatment strategies. Symptomatic treatment—such as cholinesterase inhibitors, augment neurotransmission—helps to improve cognitive performance. On the other hand, disease-modifying treatment strategies promote neuronal survival. Treatments that increase the generation or effectiveness of neurotrophic factors might help to promote neuronal survival in the face of multiple stressors. This chapter discusses the anti-inflammatory and antioxidant treatment strategies that fall into the latter category so as to improve neuronal survival in the face of nonspecific neurodegenerative stresses. It is always necessary to develop targeted anti-inflammatory strategies. Specific inflammatory processes that contribute to neuronal failure must be identified so that selective interventions can be effectively designed.