Comparative Study of the Rat-Labeled PKH26-MSCs and Its Derived Exosomes as a Neurotherapeutic Approach on LPS-Induced Alzheimer’s Disease

Purpose

Alzheimer’s disease is a common neuroinflammatory and neurodegenerative disorder with no curative therapy. This study aimed to compare the effects of bone marrow mesenchymal stem cells (MSCs) and their derived exosomes on the cognitive and neurological dysfunctions in LPS-induced Alzheimer in rats.

Materials and Methods

Forty male albino rats were divided into four equal groups: group I, control (C); group II, Alzheimer (ALZ), rats ip injected with LPS (250 µg/kg) for 5 consecutive days. Group III, MSCs Alzheimer (ALZ/MSCs), rats received LPS as group II; then, on the 5th day, they received a single iv PKH26 dye–labeled MSCs in a dose of 1 × 10⁶ cells. Group IV, MSC-derived exosomes (ALZ/exosomes), rats were received LPS as group II; then, on the 5th day, they received a single iv PKH26 dye–labeled MSC-derived exosomes in a dose of 100 µg total protein. Behavioral assessments were done; hippocampal amyloid-β peptides, acetylcholine, TNFα, BAX, Bcl2, serum MDA, and SOD were measured. Brain and hippocampus histopathological studies were done.

Results

BM-MSC/MSC-derived exosomes improved cognitive and locomotor deficits in LPS-injected rats through their homing ability. They suppressed serum MDA, hippocampal amyloid beta peptide, pro-apoptotic BAX, and pro-inflammatory TNF-α levels and restored hippocampal pyramidal cells of Cornu Ammonis compared to the ALZ. group. These levels reached the control levels only in the ALZ./exosomes group.

Conclusion

Exosomes, a cell-free therapy with homing ability, offer a promising neurotherapeutic approach for Alzheimer disorders being more effective than BM-MSCs in mitigating cognitive deficits, oxidative and apoptotic states, suppression of neuroinflammation, and amyloidogenesis.

Lay Summary

Alzheimer’s disease is a common progressive neurodegenerative disorder characterized by loss of memory and cognitive dysfunction that eventually disrupt daily activities. This study aimed to offer a promising neurotherapeutic approach for Alzheimer’s disease, comparing between the effects of bone marrow mesenchymal stem cells (MSCs) and their derived exosomes on the cognitive and neurological dysfunctions in lipopolysaccharide (LPS)-induced Alzheimer in rats. Stem cell–derived exosomes were more effective than bone marrow–derived mesenchymal stem cells in mitigating spatial learning and memory, contextual memory, and locomotor activity in LPS-induced Alzheimer’s disease. Exosomes were able to cross the blood–brain barrier and home to inflamed brain tissue exerting anti-inflammatory effects which cut off the vicious circle created by the interplay between inflammation, oxidative stress, apoptosis, and amyloid Aβ peptide. They increased hippocampal acetylcholine and restored hippocampal neurons as proved by the histopathological studies. Stem cell–derived exosomes are a cell-free anti-inflammatory therapy that can reach the brain tissue serving as a preferred promising neuroprotective management to Alzheimer’s disease.

Graphical Abstract