Oxidative Stress and Beta Amyloid in Alzheimer's Disease. Which Comes First: The Chicken or the Egg?

The pathogenesis of Alzheimer's disease involves β amyloid (Aβ) accumulation known to induce synaptic dysfunction and neurodegeneration. The brain's vulnerability to oxidative stress (OS) is considered a crucial detrimental factor in Alzheimer's disease. OS and Aβ are linked to each other because Aβ induces OS, and OS increases the Aβ deposition.

Estrogens Inhibit Amyloid-β-Mediated Paired Helical Filament-Like Conformation of Tau Through Antioxidant Activity and miRNA 218 Regulation in hTau Mice.

Background: The risk of developing Alzheimer's disease as well as its progression and severity are known to be different in men and women, and cognitive decline is greater in women than in men at the same stage of disease and could be correlated at least in part on estradiol levels.

Objective: In our work we found that biological sex influences the effect of amyloid-β42 (Aβ42) monomers on pathological tau conformational change.

Methods: In this study we used transgenic mice expressing the wild-type human tau (hTau) which were subjected to intraventricular (ICV) injections of Aβ peptides in nanomolar concentration.

α-Synuclein RT-QuIC assay in cerebrospinal fluid of patients with dementia with Lewy bodies.

We applied RT-QuIC assay to detect α-synuclein aggregates in cerebrospinal fluid (CSF) of patients with suspected Creutzfeldt-Jakob disease who had a neuropathological diagnosis of dementia with Lewy bodies (DLB) (n = 7), other neurodegenerative diseases with α-synuclein mixed pathology (n = 20), or without Lewy-related pathology (n = 49). The test had a sensitivity of 92.9% and specificity of 95.

Stroke and Amyloid-β Downregulate TREM-2 and Uch-L1 Expression that Synergistically Promote the Inflammatory Response.

Neuroinflammation is involved in the pathogenesis of Alzheimer's disease, and the transcription factor NF-κB is a player in this event. We found here that the ischemic damage alone or in association with Aβ1-42 activates the NF-κB pathway, induces an increase of BACE1 and a parallel inhibition of Uch-L1 and TREM2, both in vitro and in vivo, in Tg 5XFAD and in human brains of sporadic AD. This mechanism creates a synergistic loop that fosters inflammation.

Frontal Variant of Alzheimer's Disease: A Report of a Novel PSEN1 Mutation.

Alzheimer's disease may mimic frontotemporal dementia. We describe a case of presenile dementia who presented with peudo-psychotic symptoms carrying a PSEN1 mutation (P355 S), which was not known to be pathogenic. PET-FDG showed bilateral frontotemporal hypometabolism, but at MRI, multiple microbleeds were detected, suggestive of amyloid angiopathy.

A silver lining for 24-hydroxycholesterol in Alzheimer's disease: The involvement of the neuroprotective enzyme sirtuin 1.

It is now established that cholesterol oxidation products (oxysterols) are involved in several events underlying Alzheimer's disease (AD) pathogenesis. Of note, certain oxysterols cause neuron dysfunction and degeneration but, recently, some of them have been shown also to have neuroprotective effects. The present study, which aimed to understand the potential effects of 24-hydroxycholesterol (24-OH) against the intraneuronal accumulation of hyperphosphorylated tau protein, stressed these latter effects.

The Unexpected Role of Aβ1-42 Monomers in the Pathogenesis of Alzheimer's Disease.

Amyloid-β (Aβ) has been proposed as a biomarker and a drug target for the therapy of Alzheimer's disease (AD). The neurotoxic entity and relevance of each conformational form of Aβ to AD pathology is still under debate; Aβ oligomers are considered the major killer form of the peptide whereas monomers have been proposed to be involved in physiological process. Here we reviewed some different effects mediated by monomers and oligomers on mechanisms involved in AD pathogenesis such as autophagy and tau aggregation.

The Decrease of Uch-L1 Activity Is a Common Mechanism Responsible for Aβ 42 Accumulation in Alzheimer's and Vascular Disease.

Alzheimer's disease (AD) is a multifactorial pathology causing common brain spectrum disorders in affected patients. These mixed neurological disorders not only include structural AD brain changes but also cerebrovascular lesions. The main aim of the present issue is to find the factors shared by the two pathologies.

Dual Mechanism of Toxicity for Extracellular Injection of Tau Oligomers versus Monomers in Human Tau Mice.

The mechanism of tau toxicity is still unclear. Here we report that recombinant tau oligomers and monomers, intraventricularly injected in mice with a pure human tau background, foster tau pathology through different mechanisms. Oligomeric forms of tau alter the conformation of tau in a paired helical filament-like manner.

Beta-amyloid 1-42 monomers, but not oligomers, produce PHF-like conformation of Tau protein.

The mechanistic relationship between amyloid β1-42 (Aβ1-42) and the alteration of Tau protein are debated. We investigated the effect of Aβ1-42 monomers and oligomers on Tau, using mice expressing wild-type human Tau that do not spontaneously develop Tau pathology. After intraventricular injection of Aβ1-42, mice were sacrificed after 3 h or 4 days.

Relationship between balance and cognitive performance in older people.

We investigated the relationship between balance and cognitive level in a group of 70 women with no definite Alzheimer's disease or mild cognitive impairment diagnosis and no impairment of daily activity. Static stabilometry and the Montreal Cognitive Assessment (MoCA) test were performed. The antero-posterior sway component was demonstrated to be the best predictor of the MoCA overall score.

Amnestic mild cognitive impairment and conversion to Alzheimer's disease: insulin resistance and glycoxidation as early biomarker clusters.

Autopsy studies have indicated brain accumulation of amyloid-β peptides as a common pathogenetic hallmark of amnestic cognitive impairment (aMCI) and overt Alzheimer's disease (AD). The pathogenesis of AD is still debated but recent reports have even designated AD as type III diabetes. This study aims to assess plasma levels of malondialdehyde, pentosidine, and insulin resistance in a group of aMCI patients, AD subjects, and age- and gender-matched controls, to confirm, beyond the accumulation of amyloid-β, the presence of a metabolic disorder, as a causative/contributive factor for AD.

Aβ1-42 monomers or oligomers have different effects on autophagy and apoptosis.

The role of autophagy and its relationship with apoptosis in Alzheimer disease (AD) pathogenesis is poorly understood. Disruption of autophagy leads to buildup of incompletely digested substrates, amyloid-β (Aβ) peptide accumulation in vacuoles and cell death. Aβ, in turn, has been found to affect autophagy.

Monomeric Aβ1-42 and RAGE: key players in neuronal differentiation.

The aggregation of amyloid-β (Aβ) peptides plays a crucial role in the onset and progression of Alzheimer's disease. Monomeric form of Aβ, indeed, could exert a physiological role. Considering the anti-oligomerization property of all-trans retinoic acid (ATRA), the involvement of monomeric Aβ1-42 in ATRA-induced neuronal differentiation has been investigated.

Survival rate in patients affected by dementia followed by memory clinics (UVA) in Italy.

People affected by dementia experienced decreased life expectancy with a 2-4 times higher risk of death at a given age compared to non-demented people. Dementia represents a major cost to health care and society in the Western world and, particularly in Italy, is projected to become a high-resource demanding chronic disease. The present study aimed to estimate the average survival rate of a group of community dwelling elderly affected by dementia in Italy, and to assess the predictive variables associated with survival length.

Adjunctive agomelatine therapy in the treatment of acute bipolar II depression: a preliminary open label study.

Purpose: The circadian rhythm hypothesis of bipolar disorder (BD) suggests a role for melatonin in regulating mood, thus extending the interest toward the melatonergic antidepressant agomelatine as well as type I (acute) or II cases of bipolar depression.

Patients And Methods: Twenty-eight depressed BD-II patients received open label agomelatine (25 mg/bedtime) for 6 consecutive weeks as an adjunct to treatment with lithium or valproate, followed by an optional treatment extension of 30 weeks. Measures included the Hamilton depression scale, Pittsburgh Sleep Quality Index, the Clinical Global Impression Scale-Bipolar Version, Young Mania Rating Scale, and body mass index.

Aβ1-42-mediated down-regulation of Uch-L1 is dependent on NF-κB activation and impaired BACE1 lysosomal degradation.

Amyloid-β 1-42 accumulation is the major pathogenetic event in Alzheimer's disease (AD), believed to be responsible for synaptic dysfunction and neuronal cell death. However, the physiologic activity of Aβ peptides remains elusive: Aβ might not only play a toxic role, but also act as a functional signaling intermediate. We recently reported that Aβ1-42 promotes BACE1 transcription through the activation of the JNK-c-jun pathway.

β-amyloid 1-42 induces physiological transcriptional regulation of BACE1.

The pathogenesis of Alzheimer's disease (AD) is only partially understood. β-amyloid (Aβ) is physiologically generated by sequential cleavage of its precursor protein by the β- and the γ-secretase and it is normally disposed of. In Alzheimer's disease, Aβ is excessively produced or less dismissed, but the hypothesis on its physiological and pathological role are heterogeneous and often discordant.

Possible influence of a non-synonymous polymorphism located in the NGF precursor on susceptibility to late-onset Alzheimer's disease and mild cognitive impairment.

The complex network of neurotrophic factors is supposed to play a role in neurodegeneration, but the effect of variations in their coding genes on susceptibility to sporadic Alzheimer's disease is not established. The mature form of nerve growth factor (NGF) derives from a precursor, proNGF, which was recently discovered to exert crucial functions in brain. We designed a case-control association study to test the hypothesis as to whether polymorphisms located in the proNGF genomic region influence the liability to Alzheimer's disease and its prodromal form, mild cognitive impairment.

The earliest stage of cognitive impairment in transition from normal aging to Alzheimer disease is marked by prominent RNA oxidation in vulnerable neurons.

Although neuronal RNA oxidation is a prominent and established feature in age-associated neurodegenerative disorders such as Alzheimer disease (AD), oxidative damage to neuronal RNA in aging and in the transitional stages from normal elderly to the onset of AD has not been fully examined. In this study, we used an in situ approachto identify an oxidized RNA nucleoside 8-hydroxyguanosine (8OHG) in the cerebral cortex of 65 individuals without dementia ranging in age from 0.3 to 86 years.

Position paper of the Italian Society for the study of Dementias (SINDEM) on the proposal of a new lexicon on Alzheimer disease.

A panel of Italian neurologists of the Italian Society for the study of Dementias (SINDEM) discussed the recently proposed new lexicon for Alzheimer disease (AD) and the related diagnostic criteria for the different phases of the disease (Preclinical AD, prodromal AD and Alzheimer's dementia) (Dubois et al. in Lancet Neurol 6:734-746, 2007; in Lancet Neurol 9:1118-1127, 2010). The aim of this discussion was to reach a consensus, among the Italian neurologists involved in the study and care of persons with dementia, in particular in reference to the potential use of the proposed diagnostic criteria in clinical practice.

Amyloid-β production: major link between oxidative stress and BACE1.

Sequential endoproteolytic cleavages operated by the γ-secretase and the β-secretase (BACE1) on the β-amyloid precursor protein result in the production of the β-amyloid (Aβ) species, with two C-terminal variants, at residue 40 or at residue 42. Accumulation in brain tissue of aggregates of Aβ42 is the major pathogenetic event in Alzheimer's disease (AD). The causes of Aβ accumulation in the common sporadic form of AD are not completely understood, but they are likely to include oxidative stress (OS).

A novel origin for granulovacuolar degeneration in aging and Alzheimer's disease: parallels to stress granules.

The phosphorylated ribosomal protein S6 (pS6) is associated with the 40S ribosomal subunit in eukaryotes and is thought to have a role in RNA storage, degradation, and re-entry into translation. In this study, we found pS6 localized to granulovacuolar degeneration (GVD) within the pyramidal neurons. Immunohistochemical analysis found that nearly 20-fold more neurons contain pS6-positive granules in Alzheimer's disease (AD) hippocampus compared with age-matched controls.