الفهرس 
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Abstract
Alzheimer’s disease, the most common form of dementia, is a neurological disorder. It is a fatal, progressive and degenerative condition that destroys brain cells. The death of brain cells causes loss of cognitive state. The disease starts mild and gets progressively worse.
Al is a known neurotoxicant that has been reported to alter the BBB under normal physiological conditions and accumulates in different brain regions and has also been reported to be involved within the etiology of several neurodegenerative diseases.
In recent decades stem cell therapy has been considered one of the most promising treatments for AD patients. Stem cells are capable of spontaneous self-renewal and subsequent differentiation into specialized cells such as neurons and glial cells.
The most commonly utilized stem cells in AD-related studies are MSCs, ESCs, iPSCs and NSCs.
MSCs are multipotent progenitors derived from different adult tissues and are capable of in vitro self-renewal. They could be clinically used in AD patients because of their less invasive systemic administration (iv) without inducing tumorigenicity or immunogenicity, besides lacking ethical concerns.
Exosomes (30–150 nm in diameter) may act as paracrine mediators between MSCs and target cells. MSC-derived exosomes can recapitulate the biological activity of MSCs, and may serve as an alternative to whole cell therapy. In contrast to the relatively large MSCs (30–60 µm in diameter), nanosized exosomes, have the potential to migrate efficiently to the target organ.
So, the present study was designed to:
- Formulate extracellular vesicles like exosomes from MSCs to manage AD symptoms in experimental animal models.
- Examine and evaluate the effect of these nano-particles ’MSC-derived exosomes’ as mechanisms of action of MSCs after infusion providing considerable advantages over their counterpart live cells, potentially reducing undesirable side effects including infusional toxicities reflecting the outcome of disease improvement.
A total of 60 adult female albino wistar rats were used. The rats were randomly assigned into two groups [normal control group & experimental ovariectomized group]. After surgical ovariectomy both groups were left for a duration of 6 weeks. Through this period seventeen rats have died. The rest (43 rats) of the rats were classified as follow:
.group I (Con. group) (8 rats): Normal Control group.
.group II (AD-induced group) (20 rats): Ovariectomized animals inoculated orally with AlCl3 (17 mg/kg b.wt /day) for 2 months after 6 weeks of surgical operation.
.group III (AD-induced group treated with exosomes) (15 rats): Alzheimer’s disease-induced animals treated (i.v) with (5*106 MSC-derived exosomes/rat/week) for 2, 4 and 6 weeks.
Sacrifices were done after 2, 4 and 6 weeks following Alzheimer induction. Autopsies were performed by ether inhalation anesthesia.
Heads of animals were removed, carefully dissected, then, brains were removed and divided into three parts, where, the first part of each brain was processed for histological & histochemical analysis (haematoxylin & eosin and Congo red technique). The second half was used for immunohistochemical analysis (GFAP and MBP stains). Finally, the last part was used for biochemical analysis (β-Amyloid 1-42, miRNA let7c and BDNF).
Histological investigations of brain tissues of AD-induced group showed neuronal degeneration; amyloid plaque formation; congestion with perivascular edema and focal gliosis in cerebrum and hippocampus compared to normal control group.
On treatment with MSC-derived exosomes for 2 weeks the previous investigations were still evident but in a less aggressive manner. While, on treatment with exosomes for 4 weeks near to normal patterns were manifested. But, following 6 weeks treatment above mentioned alterations re-appeared but to less extinct than that showed at brain tissues of group II (AD-induced group).
Immuno-histochemical results showed an increase in the level of GFAP and a decrease in the MBP level in AD-induced group compared to control group. In treated group with MSC-derived exosomes for 2 and 4 weeks there was a significant decrease in GFAP level and an increase in MBP ,but, after treatment with exosomes for 6 weeks a strong significant immune-positive staining in astrocytes and most likely degenerated myelin sheath were shown but to less extinct than that showed in brain tissues of AD-induced group.
Biochemical investigations recorded significant elevation in β-Amyloid 1-42 and miRNA let7c levels and significant reduction in BDNF brain level compared to normal control group. On treatment with MSC-derived exosomes mild improvement in these levels was seen after 2 weeks and near to normal improvement after treatment for 4 weeks. On the other hand, treatment for 6 weeks showed limited improvement in these parameters validating pre-mentioned histological parameters.
In conclusion, the present study emphasizes on the vital role of AlCl3 in pathogenesis of Alzheimer. Initiation of MSC-derived exosomes may attribute to overcome such therapeutic drawback and induce new methodologies to treat neurodegenerative diseases as AD.
Besides the compelling possibility of using them as biomarkers, exosomes could be engineered to be targeted to particular cell types improving the specificity of treatment and thus reducing the incidence of side effects.