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Alzheimer's disease is one of the most common forms of dementia in the elderly. One of its hallmarks is the abnormal aggregation and deposition of β-amyloid (Aβ). Endogenous and exogenous metal ions seem to influence β-amyloid folding process, aggregation and deposition. Besides these variables other elements appear to affect β-amyloid behavior, such as cholesterol. The physiological concentration of cholesterol in the cerebrospinal fluid (CSF) was used in order to determine the extent in which Aβ and Aβ–metal complexes in vitro aggregation and their toxicity on human neuroblastoma cell cultures is affected. Cholesterol did not appear to influence Aβ and Aβ–metal complexes aggregation, but it was effective in protecting neuroblastoma cells against Aβ complexes' toxicity. The Aβ–Al complex seemed to be the most effective in disrupting and damaging membrane external layer, and simultaneously it appears to increase its toxicity on cell cultures; both of these effects are preventable by cholesterol. The presence in physiological concentrations of cholesterol seemed to compensate membrane damage that occurred to neuroblastoma cells. These findings appear to contradict some data reported in literature. We believe that our results might shed some light on the role played by cholesterol at physiological concentrations in both cellular balance and membrane protection.

Alzheimer’s disease is a multifactorial neurodegenerative disorder characterized by the pathological brain deposition of neurofibrillary tangles and senile plaques. The latter consist mainly of insoluble β-amyloid (Aβ) fibril deposition. Aβ aggregation and deposition can be increased by several factors, including metal ions. In this study we investigated the role played by metal ions in affecting Aβ oligomerization in the presence and in the absence of its hydrophobic fragment Aβ17–28. This was done not as a physiological investigation, but as a paradigmatic study to confirm the key role of Aβ superficial hydrophobicity as a relevant aggravating factor that contributes to the toxicity of Aβ and Aβ–metal complexes. The structural conformations of Aβ–metal complexes were monitored through fluorescence and turbidity measurements as well as transmission electron microscopy. Results reported herein indicate that various metals differentially influence Aβ conformation, with aluminum being the only metal ion for which we are able to determine a dramatic enhancement of peptide oligomer formation with a consequent toxic effect. This scenario was further enhanced by the presence of Aβ17–28, which resulted in a marked toxicity in a neuroblastoma cell culture as a consequence of the enhancement of the hydrophobicity of the amyloid and amyloid–metal complexes.

Excessive and sustained exposure to glutamate leads to injurious elevations of cytosolic calcium ([Ca(2+)]i), generation of reactive oxygen and nitrogen species (ROS, RNS), mitochondrial failure, mobilization of intracellular zinc ([Zn(2+)]i), and, ultimately, neuronal death. The relative contribution and temporal dynamics of the activation of these processes to promote the full development of excitotoxicity are still not completely understood. In this study, we exploited the unique features of nNOS positive neurons [nNOS (+)], a striatal subpopulation that is constitutively spared from NMDAR-dependent insults, and dissected NMDAR-driven [Ca(2+)]i, [Zn(2+)]i, ROS, and mitochondrial changes occurring in these neurons and the overall population of nNOS (-) striatal neurons. Comparing the two populations and employing pharmacological, biochemical, and single-cell imaging techniques, we show that [Zn(2+)]i mobilization acts as a critical intermediate in the cascade that links NMDAR-mediated ROS overproduction, mitochondrial failure, and [Ca(2+)]i deregulation to the production of neuronal damage. Results of this study may also provide the rationale for aiming at therapeutic agents that favor Zn(2+) homeostasis for the treatment of acute or chronic neurological conditions associated with excitotoxicity.

Cognitive impairment is the final outcome of a complex network of molecular mechanisms ultimately leading to dementia. Despite major efforts aimed at unraveling the molecular determinants of dementia of Alzheimer type (DAT), effective disease-modifying approaches are still missing. An interesting and still largely unexplored avenue is offered by nutraceutical intervention. For instance, robust epidemiological data have suggested that moderate intake of red wine may protect against several age-related pathological conditions (i.e.: cardiovascular diseases, diabetes, and cancer) as well as DAT-related cognitive decline. Wine is highly enriched in many polyphenols, including resveratrol. Resveratrol is a well recognized antioxidant which may modulate metal ion deregulation outcomes as well as main features of the Alzheimer’s disease (AD) brain. The review will discuss the potentiality of resveratrol as a neuroprotectant in dementia in relation to the oxidative stress produced by amyloid and metal dysmetabolism.

Alzheimer’s disease (AD) is a multifactorial neurological condition associated with a genetic profile that is still not completely understood. In this study, using a whole gene microarray approach, we investigated age-dependent gene expression profile changes occurring in the hippocampus of young and old transgenic AD (3xTg-AD) and wild-type (WT) mice. The aim of the study was to assess similarities between aging- and AD-related modifications of gene expression and investigate possible interactions between the two processes. Global gene expression profiles of hippocampal tissue obtained from 3xTg-AD and WT mice at 3 and 12 months of age (m.o.a.) were analyzed by hierarchical clustering. Interaction among transcripts was then studied with the Ingenuity Pathway Analysis (IPA) software, a tool that discloses functional networks and/or pathways associated with sets of specific genes of interest. Cluster analysis revealed the selective presence of hundreds of upregulated and downregulated transcripts. Functional analysis showed transcript involvement mainly in neuronal death and autophagy, mitochondrial functioning, intracellular calcium homeostasis, inflammatory response, dendritic spine formation, modulation of synaptic functioning, and cognitive decline. Thus, overexpression of AD-related genes (such as mutant APP, PS1, and hyperphosphorylated tau, the three genes that characterize our model) appears to favor modifications of additional genes that are involved in AD development and progression. The study also showed overlapping changes in 3xTg-AD at 3 m.o.a. and WT mice at 12 m.o.a., thereby suggesting altered expression of aging-related genes that occurs earlier in 3xTg-AD mice.

Many molecular modifications such as senile plaques and neurofibrillary tangles are known to be associated with Alzheimer’s disease and other neurodegenerative diseases. In this connection, metal dyshomeostasis has aroused great interest and considerable support in recent years as relevant pathological cofactors of neurodegeneration. It has been largely demonstrated both in vivo and in vitro that aberrant metal ion metabolism can lead to the development and/or worsening of several neurological disorders. In this chapter, we will focus recent biophysical findings on β-amyloid structural modifications triggered by metal ions and we will provide insights into the biological consequences of these phenomena.