amyloid-beta-peptides and Brain-Neoplasms

Immunostaining with specific antibodies has shown that innate amyloid beta (Aβ) is accumulated naturally in glioma tumors and nearby blood vessels in a mouse model of glioma. In immunofluorescence images, Aβ peptide coincides with glioma cells, and enzyme-linked immunosorbent assay (ELISA) have shown that Aβ peptide is enriched in the membrane protein fraction of tumor cells. ELISAs have also confirmed that the Aβ(1-40) peptide is enriched in glioma tumor areas relative to healthy brain areas. Thioflavin staining revealed that at least some amyloid is present in glioma tumors in aggregated forms. We may suggest that the presence of aggregated amyloid in glioma tumors together with the presence of Aβ immunofluorescence coinciding with glioma cells and the nearby vasculature imply that the source of Aβ peptides in glioma can be systemic Aβ from blood vessels, but this question remains unresolved and needs additional studies.

Topics: Amyloid beta-Peptides; Animals; Brain Neoplasms; Cell Line, Tumor; Glioblastoma; Mice; Mice, Inbred C57BL; Peptide Fragments

Alzheimer disease (AD) is characterized by chronic neuroinflammation, which may lead to dysfunction in neuronal circuits. Although reactive microglia are found in association with accumulation of beta amyloid (Aβ) plaques in the AD brain, their contribution to neuronal cell loss remains speculative. A major genetic risk factor for sporadic AD is inheritance of the apolipoprotein (apo) E4 allele, which has been shown to contribute significantly to neurodegeneration in AD. Many studies have documented the ability of Aβ fibrils in vitro to induce microglia to undergo phenotypic activation, which results in the secretion and/or expression of a plethora of free radicals and pro-inflammatory mediators. These mediators, such as reactive nitrogen/oxygen species and IL-1β as well as cyclooxygenase-2 (COX-2) with associated prostaglandin E2 (PGE(2)), are believed to be neurotoxic and to contribute to the underlying cause of AD. We have used the human H4 neuroglioma cells as a model astroglial system to examine the interactions between IL-1β and nitric oxide (NO) as co-stimulators of Aβ(1-40) in enhancing the expression of COX-2 and production of PGE(2) in the presence of recombinant human apolipoprotein E4 (apoE4). Neither Aβ(1-40) nor its reverse sequence analog Aβ(40-1) alone had a significant effect on COX-2 expression and PGE(2) production in the cells. In contrast, after co-incubation with apoE4, Aβ(1-40) increased IL-1β-induced COX-2 expression and PGE(2) production. Aβ(12-28), which binds with high affinity to apoE4, blocked apoE4-mediated effects on Aβ(1-40). Furthermore, (±)-S-Nitroso-N-acetylpenicillamine (SNAP), an agent that releases nitric oxide (NO) in situ, alone did not affect IL-1β-induced COX-2 expression, but increased PGE(2) production only. Addition of Aβ(1-40) preincubated with apoE4 to H4 cells in the presence of SNAP led to an additive IL-1β-induced COX-2 expression and PGE(2) production. These observations indicate that increased PGE(2) resulted from increased nitrosative stress, which is enhanced by apoE4. Thus a molecular understanding of the interactions of apoE4 with Aβ, NO and IL-1β on the regulation of the COX-2/prostaglandin pathway may open new avenues in understanding the mechanism of development of neurodegenerative disease such as AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Brain Neoplasms; Cell Line, Tumor; Cell Survival; Cyclooxygenase 2; Glioma; Humans; Interleukin-1beta; Nerve Degeneration; Nitric Oxide; Peptide Fragments