Abstract
Alzheimer disease (AD) is a complex neurodegenerative disorder with no definite treatment. The expression of miR-29 family is significantly reduced in AD, suggesting a part for the family members in pathogenesis of the disease. The recent emergence of microRNA (miRNA)–based therapeutic approaches is emphasized on the efficiency of miRNA transfer to target cells. The endogenously made secretory vesicles could provide a biological vehicle for drug delivery. Characteristics such as small sizes, the ability to cross the blood–brain barrier, the specificity in binding to the right target cells, and most importantly the capacity to be engineered as drug carriers have made exosomes desirable vehicles to deliver genetic materials to the central nervous system. Here, we transfected rat bone marrow mesenchymal stem cells and HEK-293T cells (human embryonic kidney 293 cells) with recombinant expression vectors, carrying either mir-29a or mir-29b precursor sequences. A significant overexpression of miR-29 and downregulation of their targets genes, BACE1 (β-site amyloid precursor protein cleaving enzyme 1) and BIM [Bcl−2 interacting mediator of cell death (BCL2-like 11)], were confirmed in the transfected cells. Then, we confirmed the packaging of miR-29 in exosomes secreted from the transfected cells. Finally, we investigated a possible therapeutic effect of the engineered exosomes to reduce the pathological effects of amyloid-β (Aβ) peptide in a rat model of AD. Aβ–treated model rats showed some deficits in spatial learning and memory. However, in animals injected with miR-29–containing exosomes at CA1 (cornu ammonis area), the aforementioned impairments were prevented. In conclusion, our findings provide a new approach for the packaging of miR-29 in exosomes and that the engineered exosomes might have a therapeutic potential in AD.
Highlights
Alzheimer disease is a chronic neurodegenerative disorder that affects the hippocampus, an area of the brain that is necessary for spatial memory formation (Mu and Gage, 2011)
The results demonstrated that both miR-29a (Figure 1A) and miR29b (Figure 1B) had been overexpressed in the transfected cells, compared to the mock-transfected or untransfected cells
Lack of inducing immune system, as well as their capacity to be engineered as drug carriers, has made exosomes desirable vehicles to deliver genetic materials to the central nervous system
Summary
Alzheimer disease is a chronic neurodegenerative disorder that affects the hippocampus, an area of the brain that is necessary for spatial memory formation (Mu and Gage, 2011). AD is hallmarked clinically by a progressive and gradual decline in cognitive function and neuropathologically by accumulation of amyloidβ (Aβ) peptides as β-amyloid plaques, the hyperphosphorylation of tau proteins, and neuronal and synaptic loss. There is still considerable debate about the cause of AD, the amyloid cascade hypothesis remains the best-defined and most studied mechanism for the disease (Selkoe, 2001; Hardy and Selkoe, 2002). According to the amyloid cascade hypothesis, which is a key event in the initiation of AD, soluble amyloid β accumulation into toxic oligomers and amyloid plaques initiates a pathogenic cascade leading to accumulation of the hyperphosphorylated tau protein in neurofibrillary tangles, reduced numbers of synapses, death of neuronal cells, mitochondrial malfunction, and eventually loss of cognitive function (Drachman, 2014). Because of the complexity of AD, few medications were clinically administered to treat this disease.
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