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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
COMPOSITIONS FOR USE IN THE PREVENTION AND/ OR TREATMENT OF INTELLECTUAL DISABILITY AND NEURODEGENERATIVE DISEASES IN A SUBJECT WITH DOWN SYNDROME
No full textDown syndrome (DS) is a condition caused by total or partial trisomy of chromosome 21, and is characterized by both physical and neurological defects, including mild to severe intellectual disability. In addition, individuals with DS have a high risk of developing neurodegenerative diseases, such as Alzheimer's disease (AD), usually starting at 40 years of age.
The recovery of the behavioral and neurophysiological deficit observed following the use of GAB AA receptor (GAB AA-R) inhibitors in mouse models of DS has led to the hypothesis that the intellectual deficit could depend on an imbalance in inhibitory circuits.
Most of the data produced so far in mouse models suggests that this imbalance may be attributable to a high number of inhibitory neurons and a higher frequency of inhibitory post-synaptic currents. At the same time, however, evidence to the contrary was also provided: in particular, the imbalance of the inhibitory circuits would cause an increase in the intracellular concentration of chlorine ions (CT) in such a way that, following activation of the GABAA receptor, a flow of Cl- ions from the inside to the outside of the cell would be observed, with consequent depolarization of the neuron and reduced inhibition.
Consequently, although alteration of GABAergic transmission is the basis of cognitive retardation in subjects with DS, the causes of this alteration are still unclear and, to date, there are no therapeutic approaches useful for improving cognitive deficit and counteracting the development of neurodegenerative diseases in individuals with DS, particularly in adulthood.
Existing products such as GABA-A receptor antagonists or reverse inhibitors are not available in the clinic; when tested on humans they did not reach the primary and secondary endpoints and the study was stopped. Furthermore, the use of broad- spectrum GABAA receptor antagonists has not been approved as they can promote convulsions and anxiety crises. Summary of the invention
The present description has the object of providing a composition that is efficient and safe for use in preventing and/or treating intellectual disability and neurodegenerative diseases in a subject with Down syndrome (DS). According to the present description, this object is achieved thanks to the subject specifically indicated in the following claims, which are intended as an integral part of this description.
One embodiment of the present description provides a composition for use in the prevention and/or in the treatment of intellectual disability and neurodegenerative diseases in a subject with DS, wherein the composition comprises - as active agent
- at least one compound belonging to the class of inhibitors of the enzyme dipeptidyl-peptidase IV (DPP4). The compound belonging to the class of DPP4 inhibitors also belongs to the class of gliptins, and may be selected in the group consisting of sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, tenegliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, glosogliptin, dutogliptin.
The present description also provides a method for treating intellectual disability and neurodegenerative diseases in a subject with DS, the method comprising the step of administering a composition to the subject comprising at least one compound belonging to the class of dipeptidyl-peptidase IV inhibitors (DPP4) as active agent.
The composition of the present description has been found to be effective not only in restoring GABAergic transmission and the cognitive deficit, but also in slowing the development of neurodegenerative diseases in subjects with DS, such as Alzheimer's disease, for example. Furthermore, the composition activates a specific molecular mechanism (described below), which in subjects with DS - unlike what has been demonstrated in healthy subjects - has been surprisingly able to promote neuroprotective (and non-neurotoxic) effects
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
Oxidative stress, protein modification and Alzheimer disease
No full textAlzheimer disease (AD) is a progressive neurodegenerative disease that affects the elderly population
with complex etiology. Many hypotheses have been proposed to explain different causes of AD, but the
exact mechanisms remain unclear. In this review, we focus attention on the oxidative-stress hypothesis
of neurodegeneration and we discuss redox proteomics approaches to analyze post-mortem human brain
from AD brain. Collectively, these studies have provided valuable insights into the molecular mechanisms
involved both in the pathogenesis and progression of AD, demonstrating the impairment of numerous
cellular processes such as energy production, cellular structure, signal transduction, synaptic function,
mitochondrial function, cell cycle progression, and degradative systems. Each of these cellular functions
normally contributes to maintain healthy neuronal homeostasis, so the deregulation of one or more of
these functions could contribute to the pathology and clinical presentation of AD. In particular, we discuss
the evidence demonstrating the oxidation/dysfunction of a number of enzymes specifically involved in
energy metabolism that support the view that reduced glucose metabolism and loss of ATP are crucial
events triggering neurodegeneration and progression of AD
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
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
Modulation of GLP-1 signaling as a novel therapeutic approach in the treatment of Alzheimer’s disease pathology
No full textMaternal exposure to low levels of corticosterone during lactation increases social play behavior in rat adolescent offspring
No full textAlthough costly in energy and time, social play is present and evolutionarily conserved in nearly all young mammals. Ontogenetic factors responsible for this particular form of supposed rewarding behavior are incompletely understood. Here, we have focused our attention on maternal glucocorticoid hormone. We used a model in which neonate rats are fed by mothers in which drinking water has been supplemented with 0.2 mg/ml corticosterone. The control groups were lactated by water-drinking mothers. Both male and female adolescent offspring of corticosterone (CORT) supplemented dams (CORT-nursed) showed an increase in social play behavior (i.e., pinning, pouncing, wrestling/boxing and social exploration) when compared to controls. No differences were observed between CORT-nursed progeny of both sexes and controls in the exploration of the arena during the social encounter. Finally, no differences were found in CORT plasma levels in basal conditions and following a social play session in both male and female CORT-nursed rats. These results indicate that variations in the maternal glucocorticoid status are able, directly or indirectly, to influence social play behavior in the offspring, although there is no direct relationship between the level of social play behavior and the intensity of adrenocortical activation
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