Denise Drago

Aluminum complexing enhances amyloid β protein penetration of blood-brain barrier

A significant co-morbidity of Alzheimers disease and cerebrovascular impairment suggests that cerebrovascular dysregulation is an important feature of dementia. Amyloid beta protein (Abeta), a relevant risk factor in Alzheimers disease, has neurotoxic properties and is thought to play a critical role in the cognitive impairments. Previously, we demonstrated that the 42mer of Abeta (Abeta42) complexed with aluminum (Al-Abeta42) is much more cytotoxic than non-complexed Abeta42. The level of Abeta in the brain is a balance between synthesis, degradation, and fluxes across the blood-brain barrier (BBB). In the present paper, we determined whether complexing with aluminum affected the ability of radioactively iodinated Abeta to cross the in vivo BBB. We found that the rates of uptake of Al-Abeta42 and Abeta42 were similar, but that Al-Abeta42 was sequestered by brain endothelial cells much less than Abeta42 and so more readily entered the parenchymal space of the brain. Al-Abeta42 also had a longer half-life in blood and had increased permeation at the striatum and thalamus. Brain-to-blood transport was similar for Al-Abeta42 and Abeta42. In conclusion, complexing with aluminum affects some aspects of blood-to-brain permeability so that Al-Abeta42 would have more ready access to brain cells than Abeta42.

Chelation therapy for neurodegenerative diseases

Mounting evidence suggests a central role for transition biometals in the etiopathogenesis of neurodegenerative diseases (ND). Indeed, while studying the molecular basis for this heterogeneous group of diseases, it has become increasingly evident that biometals and nonphysiological Al are often involved in pathology onset and progression, either by affecting the conformation of specific proteins or by exacerbating local oxidative stress. The apparently critical role played by metal dishomeostasis in ND makes chelation therapy an attractive pharmacological option. However, classical metal chelation approaches, relying on potent metal ligands, turned out to be successful only in those rare cases where exceptional brain metal accumulation occurs due to specific defects in metal metabolism. In contrast, metal‐targeted approaches using ligand of intermediate strength seem to be more appropriate in fighting the major ND, although their benefits are still questioned. We report here a survey of recent evidences supporting the use of a variety of metal ligands, and even functionalized nanoparticles, for the treatment of the most common ND. The beneficial neuropharmacological actions of metal‐targeted agents most likely arise from local metal redistribution rather than from massive metal removal. The perspectives for the development of new effective agents against ND are critically discussed.

Accumulation of copper and other metal ions, and metallothionein I/II expression in the bovine brain as a function of aging

Accumulation of metal ions in the brain contributes to heighten oxidative stress and neuronal damage as evidenced in aging and neurodegenerative diseases, both in humans and in animals. In the present paper we report the analysis of Cu, Zn and Mn in the brain of two series of respectively young (8-16 months) and adult (9-12 years) bovines. Our data indicate that the concentrations of Cu varied of one order of magnitude between 1.67 and 15.7microg/g wet tissue; the levels of Zn varied between 6.13 and 17.07microg/g wet tissue and the values of Mn resulted between 0.19 and 1.24microg/g wet tissue. We found relevant age-dependent differences in the distribution of Cu and Zn, whose concentrations were markedly higher in older animals. By contrast, Mn seemed to redistribute in the different cerebral areas rather than drastically change with age. Tissues from bovine brain were also analysed immunohistochemically for the presence and distribution of metallothionein I/II and also for the expression of glial fibrillary acidic protein. Metallothionein I/II immunoreactive elements included ependymal cells lining the lateral ventricles and neural cells in middle layer of the cerebellar cortex. No age differences were evident between calves and adult. The presence of liquor-contacting metallothionein I/II in cells confirms that their functions in the central nervous system are not yet completely established.

Microarray Analysis on Human Neuroblastoma Cells Exposed to Aluminum, β1–42-Amyloid or the β1–42-Amyloid Aluminum Complex

Background A typical pathological feature of Alzheimers disease (AD) is the appearance in the brain of senile plaques made up of β-amyloid (Aβ) and neurofibrillary tangles. AD is also associated with an abnormal accumulation of some metal ions, and we have recently shown that one of these, aluminum (Al), plays a relevant role in affecting Aβ aggregation and neurotoxicity. Methodology In this study, employing a microarray analysis of 35,129 genes, we investigated the effects induced by the exposure to the Aβ1–42-Al (Aβ-Al) complex on the gene expression profile of the neuronal-like cell line, SH-SY5Y. Principal Findings The microarray assay indicated that, compared to Aβ or Al alone, exposure to Aβ-Al complex produced selective changes in gene expression. Some of the genes selectively over or underexpressed are directly related to AD. A further evaluation performed with Ingenuity Pathway analysis revealed that these genes are nodes of networks and pathways that are involved in the modulation of Ca2+ homeostasis as well as in the regulation of glutamatergic transmission and synaptic plasticity. Conclusions and Significance Aβ-Al appears to be largely involved in the molecular machinery that regulates neuronal as well as synaptic dysfunction and loss. Aβ-Al seems critical in modulating key AD-related pathways such as glutamatergic transmission, Ca2+ homeostasis, oxidative stress, inflammation, and neuronal apoptosis.

Microarray analysis of human neuroblastoma cells exposed to beta-amyloid, aluminum, and the beta-amyloid-aluminum complex

with amnestic mild cognitive impairment (MCI) were examined by gender and genotype. Results: In early AD, male gender and butyrylcholinesterase (BuChE)-K carrier status, if accompanied by apolipoprotein E (APOE) e4 carrier status, results in prominent damage to grey and white matter in the medial temporal region and cognitive decline due to direct toxic effects of aggregated Ab on cholinergic synapses, neurons, myelin and oligodendrocytes. Symptoms can be attenuated by increasing synaptic acetylcholine (ACh) in damaged, but still functional, cholinergic synapses. Conversely, chronic glial overactivation, that is more likely in females and due, at least in part, to extracellular ACh deficits, can also drive neurodegenerative processes. In females with wild-type BuChE, glial overactivation may be the main driver from MCI to AD. Females are more likely than males to have accelerated age-related myelin breakdown, more widespread white matter loss, loss of neural network connectivity, whole brain atrophy and functional decline. Damage to neural network connectivity can be attenuated by increasing extracellular ACh and this is disease-modifying. Conclusions: Identification of phenotypes is important to appropriately target dementia therapy and interpret biomarker data. Preservation of the functional integrity of the neural network may be an important component of strengthening cognitive reserve and significantly delaying the onset and progression of dementia, particularly in females. Prospective confirmation of these hypotheses is required.

Acidic vesicles of the endo-exocytic pathways as targets for some anti-monoamine oxidase drugs

Acidic vesicles are cytoplasmatic organelles delimited by a single lipoprotein membrane. They contain a large number of enzymes, mostly acidic hydrolases, catalysing various reactions at optimal acidic pH, capable of participating in intracellular digestion. In this paper, some anti-monoamine oxidase drugs (clorgyline, pargyline, amantadine and deprenyl), utilized as pharmacological treatment in some neurological disorders (e.g., Alzheimer’s, Parkinson’s etc. diseases), were tested for their ability to influence the pH of the acidic intracellular organelles with the aim of exploring their possible pharmacological action. Of the above mentioned drugs, clorgyline showed the most effective action in modifying the acidic vesicles’ internal pH, followed by deprenyl, pargyline and amantadine. The effect was not ascribed to an increased proton conductance, but was most likely due to a weak base-like mechanism, in that they exhibit equilibria among species associated with H+ ions and species lacking this association.