1,721,080 research outputs found
Borsa per soggiorno all'estero
No full textBorsa di studio post-dottorato dell'Istituto Pasteur- Fondazione Cenci Bolognetti per progetti di ricerca all'estero della durata di un anno con possibilità di rinnovo per un ulteriore ann
Cathepsin D as a therapeutic target in Alzheimer’s disease
Full text linkSeveral neurodegenerative diseases are characterized by the accumulation of ubiquitin-positive protein aggregates in affected brain
regions [1]. These misfolded/aberrant proteins are toxic for neuronal function and contribute to neurodegeneration. Protein quality
control, including autophagy and proteasome system, is necessary
for the removal of aggregated proteins that are harmful for the
brain. Autophagy-lysosomal system plays crucial roles in both
normal cellular homeostasis and disease states. Indeed, the constitutively active autophagy is critical for post-mitotic cells, such as
neurons that cannot simply dilute harmful molecules through cell
division [2]. The lysosomal system consists of communicating
acidic compartments which contain over 80 lysosomal hydrolases,
including proteases, nucleases, phosphatases, sulfatases, lipases,
and glycosidase. Lysosomal cathepsins can be divided into three
groups: cysteine (cathepsins B, C, F, H, K, L, O, S, V, W, and X),
aspartic (cathepsins D and E), and serine (cathepsin G) proteases
[3]. The aspartic cathepsin D and some of the cysteine cathepsins
are ubiquitous and among the most abundant lysosomal proteases. The acidic environment of the lysosomal lumen, resulting
from the action of the vacuolar H+
-ATPase, facilitates the degradation process by loosening the structures of macromolecules and is
optimal for the activity of lysosomal hydrolases [3].
In the Alzheimer’s disease (AD) brain, progressive abnormalities of the endosomal-lysosomal system, such as increase in
size and volume of early endosomes, are a prominent neuropathological feature [2]. Amyloid beta (Aβ) peptide has also
been detected in these enlarged endosomes that are immunopositive for the early endosomal marker rab5 [4]. Indeed,
several studies have identified the endosomal-lysosomal pathway as an important regulator of the processing of amyloid
precursor protein (APP) [5]. Early endosomes produce Aβ from
APP in normal cells and mediate the uptake of Aβ and soluble
APP. The upregulation of the lysosomal system occurs in
vulnerable cell populations and results in increased numbers
of lysosomes with elevated expression of lysosomal hydrolases
[6]. As AD pathogenesis progresses, lysosomal dysfunction
appears to occur with the build-up of vacuolar structures
and the accumulation of Aβ. The degeneration of the compromised neurons leads to the release of these structures into
the extracellular space, where they associate with deposits
of A
Biliverdin Reductase-A correlates with inducible nitric oxide synthasein in atorvastatin treated aged canine brain.
No full textAlzheimer's disease is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Recent preclinical and epidemiological studies proposed statins as a possible therapeutic drug for Alzheimer's disease, but the exact mechanisms of action are still unknown. Biliverdin reductase-A is a pleiotropic enzyme involved in cellular stress responses. It not only transforms biliverdin-IX alpha into the antioxidant bilirubin-IX alpha but its serine/threonine/tyrosine kinase activity is able to modulate cell signaling networks. We previously reported the beneficial effects of atorvastatin treatment on biliverdin reductase-A and heme oxygenase-1 in the brains of a well characterized pre-clinical model of Alzheimer's disease, aged beagles, together with observed improvement in cognition. Here we extend our knowledge of the effects of atorvastatin on inducible nitric oxide synthase in parietal cortex, cerebellum and liver of the same animals. We demonstrated that atorvastatin treatment (80 mg/day for 14.5 months) to aged beagles selectively increased inducible nitric oxide synthase in the parietal cortex but not in the cerebellum. In contrast, inducible nitric oxide synthase protein levels were significantly decreased in the liver. Significant positive correlations were found between biliverdin reductase-A and inducible nitric oxide synthase as well as heme oxygenase-1 protein levels in the parietal cortex. The opposite was observed in the liver. Inducible nitric oxide synthase up-regulation in the parietal cortex was positively associated with improved biliverdin reductase-A functions, whereas the oxidative-induced impairment of biliverdin reductase-A in the liver negatively affected inducible nitric oxide synthase expression, thus suggesting a role for biliverdin reductase-A in atorvastatin-dependent inducible nitric oxide synthase changes. Interestingly, increased inducible nitric oxide synthase levels in the parietal cortex were not associated with higher oxidative/nitrosative stress levels. We hypothesize that biliverdin reductase-A-dependent inducible nitric oxide synthase regulation strongly contributes to the cognitive improvement observed following atorvastatin treatment.Alzheimer's disease is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Recent preclinical and epidemiological studies proposed statins as a possible therapeutic drug for Alzheimer's disease, but the exact mechanisms of action are still unknown. Biliverdin reductase-A is a pleiotropic enzyme involved in cellular stress responses. It not only transforms biliverdin-IX alpha into the antioxidant bilirubin-IX alpha but its serine/threonine/tyrosine kinase activity is able to modulate cell signaling networks. We previously reported the beneficial effects of atorvastatin treatment on biliverdin reductase-A and heme oxygenase-1 in the brains of a well characterized pre-clinical model of Alzheimer's disease, aged beagles, together with observed improvement in cognition. Here we extend our knowledge of the effects of atorvastatin on inducible nitric oxide synthase in parietal cortex, cerebellum and liver of the same animals. We demonstrated tha
Targeting mTOR to reduce Alzheimer-related cognitive decline: from current hits to future therapies
No full textIntroduction: The mTOR pathway is involved in the regulation of a wide repertoire of cellular functions in the brain and its dysregulation is emerging as a leitmotif in a large number of neurological disorders. In AD, altered mTOR signaling contributes to the inhibition of autophagy deposition of Aβ and tau aggregates and to the alteration of several neuronal metabolic pathways.
Areas covered: In this review, we report all the current findings on the use of mTOR inhibitors (rapamycin, rapalogues) in the treatment of AD. These results support the role of mTOR inhibitors as potential therapeutic agents able to reduce AD hallmarks and recover cognitive performances.
Expert commentary: Despite mTOR inhibitors appearing to be ideal compounds to counteract AD, further studies are needed in order to gain knowledge on the involvement of aberrant mTOR in AD, and to standardize a valuable therapeutic approach that can be translated to humans
Role of 4-hydroxy-2-nonenal (HNE) in the pathogenesis of Alzheimer disease and other selected age-related neurodegenerative disorders
No full textOxidative stress is involved in various and numerous pathological states including several age-related neurodegenerative diseases. Peroxidation of the membrane lipid bilayer is one of the major sources of free radical-mediated injury that directly damages neurons causing increased membrane rigidity, decreased activity of membrane-bound enzymes, impairment of membrane receptors and altered membrane permeability and eventual cell death. Moreover, the peroxidation of polyunsaturated fatty acids leads to the formation of aldehydes, which can act as toxic by-products. One of the most abundant and cytotoxic lipid -derived aldehydes is 4-hydroxy 2-nonenal (HNE). HNE toxicity is mainly due to the alterations of cell functions by the formation of covalent adducts of HNE with proteins. A key marker of lipid peroxidation, HNE-protein adducts, were found to be elevated in brain tissues and body fluids of Alzheimer disease, Parkinson disease, Huntington disease and amyotrophic lateral sclerosis subjects and/or models of the respective age-related neurodegenerative diseases. Although only a few proteins were identified as common targets of HNE modification across all these listed disorders, a high overlap of these proteins occurs concerning the alteration of common pathways, such as glucose metabolism or mitochondrial function that are known to contribute to cognitive decline. Within this context, despite the different etiological and pathological mechanisms that lead to the onset of different neurodegenerative diseases, the formation of HNE-protein adducts might represent the shared leit-motif, which aggravates brain damage contributing to disease specific clinical presentation and decline in cognitive performance observed in each case
Unraveling the complexity of neurodegeneration in brains of subjects with Down syndrome: insights from proteomics.
No full textDown syndrome (DS) is one of the most common genetic causes of intellectual disability characterized by multiple pathological phenotypes, among which neurodegeneration is a key feature. The neuropathology of DS is complex and likely results from impaired mitochondrial function, increased oxidative stress, and altered proteostasis. After the age of 40 years, many (most) DS individuals develop a type of dementia that closely resembles that of Alzheimer's disease with deposition of senile plaques and neurofibrillary tangles. A number of studies demonstrated that increased oxidative damage, accumulation of damaged/misfolded protein aggregates, and dysfunction of intracellular degradative systems are critical events in the neurodegenerative processes. This review summarizes the current knowledge that demonstrates a “chronic” condition of oxidative stress in DS pointing to the putative molecular pathways that could contribute to accelerate cognition and memory decline. Proteomics and redox proteomics studies are powerful tools to unravel the complexity of DS phenotypes, by allowing to identifying protein expression changes and oxidative PTMs that are proved to be detrimental for protein function. It is reasonable to suggest that changes in the cellular redox status in DS neurons, early from the fetal period, could provide a fertile environment upon which increased aging favors neurodegeneration. Thus, after a critical age, DS neuropathology can be considered a human model of early Alzheimer's disease and could contribute to understanding the overlapping mechanisms that lead from normal aging to development of dementia
Pathological role of PI3K/AKT/mTOR signaling pathway in Down Syndrome brain
No full textDown syndrome (DS) is the most frequent chromosomal abnormality that causes intellectual disability. The neuropathology of DS is complex and includes development of Alzheimer disease (AD). The accumulation of amyloid beta (Aβ)-peptide in DS brain can be observed as early as 8–12 years of age. Interestingly, the incidence of dementia typically does not increase until adults with DS are over the age 50 years. Within this context, it has been suggested that DS may serve as a model for the study the early molecular events in the pathogenesis and progression of AD neuropathology. The aim of our study is to gain new insights in the molecular mechanisms impaired in DS subjects that eventually lead to the development of AD-like dementia. In particular we focused our work on the evaluation of PI3K/Akt/mTOR axis in the frontal cortex from DS subjects (under the age of 40 ) and DS
with AD compared with age-matched controls (Young and Old). The PI3K/Akt/mTOR axis control several
key pathways involved in DS neuropathology and progression to AD and, if aberrantly regulated, affect Aβ deposition and tau phosphorylation
- …
