Gianfranco Olivieri

Red wine ingredient resveratrol protects from β-amyloid neurotoxicity

Background: β-Amyloid peptide (Aβ), a neutrotoxic substance, has been implicated to a great degree in cell death during the course of AD. Resveratrol, a natural polyphenol mainly found in red wine, has been shown to be cardioprotective and chemoprotective. Since a moderate wine intake correlates with a lower risk for Alzheimer disease (AD), an additional neuroprotective effect has been postulated for resveratrol. Objective: The present study aimed at elucidating the possible neuroprotective effects of resveratrol against Aβ-induced neurotoxicity. Methods: The neuroprotective capacity against Aβ-related oxidative stress was studied in a cell culture model suitable for studying such potentially neuroprotective substances. Results: Resveratrol maintains cell viability and exerts an anti-oxidative action by enhancing the intracellular free-radical scavenger glutathione. Conclusion: Our findings suggest that red wine may be neuroprotective through the actions of resveratrol.

Cortical alterations of angiotensin converting enzyme, angiotensin II and AT1 receptor in Alzheimer’s dementia

We investigated the immunohistochemical alterations of angiotensin converting enzyme (ACE), angiotensin II and AT1 receptor in the parietal cortex in Alzheimers dementia (AD) to reveal the contributive role of the brain renin-angiotensin system in the disease process. In controls, ACE, angiotensin II and AT1 immunoreactivities were localized to pyramidal neurons of the cortex. The staining intensity was distinctly increased in AD for all three antigens, involving predominantly cortical layer V, which may reflect the enhanced brain renin-angiotensin system activity in the disease process. In addition, a prominent perivascular ACE and angiotensin II immunoreactivity surrounding some cortical vessels in aged controls and AD patients points to an underlying microvascular pathology in the process of neurodegeneration.

Increased melatonin 1a-receptor immunoreactivity in the hippocampus of Alzheimer's disease patients.

The pineal secretory product melatonin has, in addition to regulating retinal, circadian and vascular functions, neuroprotective effects. Blood melatonin levels are often decreased in Alzheimers disease (AD), a progressively disabling neurodegenerative disorder. In this study we provide the first immunohistochemical evidence for the localization of melatonin 1a‐receptor (MT1) in aged human hippocampus and a comparison of AD cases. MT1 was localized to pyramidal neurons in the hippocampal cornu ammonis (CA)1‐4 subfields. There was a distinct increase in staining intensity in all AD cases indicating an up‐regulation of the receptor, possibly as a compensatory response to impaired melatonin levels in order to augment melatonins neuroprotective effects.

Hippocampal estrogen β-receptor immunoreactivity is increased in Alzheimer's disease

Abstract Post-menopausal estrogen use reduces the risk and severity of Alzheimer’s disease (AD). The present study investigates the distribution of both estrogen receptors ERα and ERβ in the human hippocampus in aged controls and in AD cases with immunohistochemistry. No ERα immunoreactivity was observed both in controls and in AD cases. On the other hand, ERβ was observed in some neuronal cells in the hippocampal subfields CA1–4, in astrocytes and in extracellular deposits both in controls and AD cases. The ERβ immunoreactivity was distinctly increased in all AD cases in cellular and extracellular localizations indicating a role for ERβ-mediated estrogen effects in AD-related neuropathology. This study provides the first demonstration of ERβ in human hippocampus in aged controls compared to AD cases.

Distribution of Melatonin MT1 Receptor Immunoreactivity in Human Retina

Melatonin is synthesized in the pineal gland and retina during the night. Retinal melatonin is believed to be involved in local cellular modulation and in regulation of light-induced entrainment of circadian rhythms. The present study provides the first immunohistochemical evidence for the localization of melatonin 1a-receptor (MT1) in human retina of aged subjects. Ganglion, amacrine, and photoreceptor cells expressed MT1. In addition, MT1 immunoreactivity was localized to cell processes in the inner plexiform layer and to central vessels of the retina, as well as to retinal vessels but not to ciliary or choroidal vessels. These results support a variety of cellular and vascular effects of melatonin in the human retina. Preliminary evidence from patients with Alzheimers disease (AD) revealed increased MT1 immunoreactivity in ganglion and amacrine cells, as well as in vessels. In AD cases photoreceptor cells were degenerated and showed low MT1 expression.

Melatonin protects SHSY5Y neuroblastoma cells from cobalt‐induced oxidative stress, neurotoxicity and increased β‐amyloid secretion

Heavy metals are increasingly being implicated as causative agents in neurodegenerative diseases such as Alzheimers disease (AD). Cobalt, a positively charged transition metal, has previously been shown to be in elevated levels in the brain of AD patients compared with age‐matched controls. In this study, we investigate the effects of cobalt as an inducer of oxidative stress/cell cytotoxicity and the resultant metabolic implications for neural cells. We show that cobalt is able to induce cell cytotoxicity (reduced MTT metabolism) and oxidative stress (reduced cellular glutathione). The pre‐treatment of cells with the pineal indoleamine melatonin, prevented cell cytotoxicity and the induction of oxidative stress. Cobalt treatment of SHSY5Y cells increased the release of β‐amyloid (Aβ) compared with untreated controls (ratio Aβ 40/42). Melatonin pre‐treatment reversed the deleterious effects of cobalt. These findings are significant as cobalt is an essential nutritional requirement, usually bound to cobalamin (vitamin B12), for all animals which in the unbound form could lead to neurotoxicity.

Cerebrovascular melatonin MT1-receptor alterations in patients with Alzheimer's disease

The pineal hormone melatonin has two major functions: as a transducer of the circadian day-night signal across the seasons, and as a vasoactive substance regulating cerebral circulation. The vasoconstrictive effects of melatonin have been postulated to be mediated by the melatonin 1a-receptor (MT1). The objective of this study was to provide the first immunohistochemical evidence for the localization of vascular MT1 in human control hippocampus compared to Alzheimers disease (AD) patients, since regional blood flow impairments contribute to the neurodegenerative course of the disease. Both superficial and intrahippocampal arteries revealed MT1 immunoreactivity in adventitia in controls, which was distinctly increased in AD patients. The increased MT1 in AD may indicate a regulatory response to impaired melatonin levels in those patients, contributing to the regulation of cerebral circulation.

Alterations in Trk A, Trk B and Trk C Receptor Immunoreactivities in Parietal Cortex and Cerebellum in Alzheimer’s Disease

The neurotrophins nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 bind to the tyrosine kinase (trk) receptors trk A, trk B and trk C, respectively, with high affinity. We investigated the expression of the trk receptors in the parietal cortex (PC) and cerebellum of patients with Alzheimer’s disease (AD) and age-matched controls. Cortical layers II–VI displayed a distinct cellular immunoreactivity for trk A and C with an emphasis in the pyramidal neurons of layers III and V. Trk B immunoreactivity was primarily located in the deeper cortical layers with a predominance in layer V. There was a decrease in trk A and C immunoreactivity in the PC of AD cases, while trk B density appeared to be unchanged. In addition, cerebellar Purkinje cells revealed a distinct immunoreactivity for trk C both in control and AD cases, suggesting trk C may be important in the maintenance of these cells in the aged brain.

Immunohistochemical localization of EphA5 in the adult human central nervous system.

To better understand the functional role of EphA5 in the adult human central nervous system (CNS), we performed an immunohistochemical mapping study. EphA5, like other members of the Elk/Eph family of receptor tyrosine kinases, was widely distributed in CNS neurons. However, the distribution of the neuronal staining was not uniform. The abundance of stained neurons appeared to increase from the forebrain to the hindbrain and spinal cord. Glial and endothelial tissue was unstained. These findings are consistent with the existence of receptor and ligand gradients in different brain regions. The localization of EphA5 to motor and sensory neurons is consistent with a role of EphA5 in neural plasticity, cell-cell recognition, and topographical orientation of neuronal systems.

Alterations in neurotrophins and neurotrophin receptors in Alzheimer’s disease

We demonstrated that nerve growth factor (NGF) levels were increased in hippocampus and cortical areas, as well as in cerebrospinal fluid (CSF) of patients with Alzheimers disease (AD). Such increases may, at least in part, be due to a decreased expression of the NGF high affinity receptor trkA. Measurement of CSF levels of NGF may add to the repertoire of potential biochemical diagnostic markers in living AD patients.