Intravenous administration of mesenchymal stem cells reduces Tau phosphorylation and inflammation in the 3xTg-AD mouse model of Alzheimer's disease

• Published in: Experimental neurology 2021-07, Vol.341, p.113706-113706, Article 113706
• Main Authors: Neves, Amanda Ferreira, Camargo, Christian, Premer, Courtney, Hare, Joshua M., Baumel, Bernard S., Pinto, Milena
• Format: Article
• Language: English
• Subjects: 3xTg-AD mice; Administration, Intravenous; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - therapy; Alzheimer's disease; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Amyloid-β; Animals; Female; Hippocampus - metabolism; Inflammation - genetics; Inflammation - metabolism; Inflammation - therapy; Mesenchymal Stem Cell Transplantation - methods; Mesenchymal Stem Cells; Mice; Mice, 129 Strain; Mice, Transgenic; Neuroinflammation; Peptide Fragments - antagonists & inhibitors; Peptide Fragments - genetics; Peptide Fragments - metabolism; Phosphorylation - physiology; Tau phosphorylation; tau Proteins - antagonists & inhibitors; tau Proteins - genetics; tau Proteins - metabolism
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2021.113706

Mesenchymal stem cell (MSC) administration is a novel and promising therapeutic approach for Alzheimer's disease (AD). Focusing on an intervention easily translatable into clinical practice, we administered allogeneic bone marrow-derived MSCs intravenously in a mouse model of AD (3xTg-AD). We systematically evaluated the effects of a single-dose and multiple-doses of MSCs in young and old mice (5 or 10 months old), comparing the short-term and long-term effects after 1, 2, or 7 months of treatment. A single dose of MSCs in young mice attenuated neuroinflammation 1 and 7 months after injection, whereas multiple-doses did not show any effect. Multiple-doses of MSCs (administered at 5 to 12 mo, or 10 to 12 mo) reduced the β-secretase cleavage of the amyloid precursor protein, although levels of Aβ-42 did not change. Most interestingly, multiple doses of MSCs affected tau hyperphosphorylation. MSCs administered in young mice for 7 months decreased the pathological tau phosphorylation at T205, S214, and T231. MSCs administered in old mice for 2 months decreased tau phosphorylation at S396. Our findings show how different timing and frequency of MSC injections can affect and modulate several aspects of the AD-like neuropathology in the 3xTg-AD mouse model, strengthening the concept of fine-tuning MSC therapy for Alzheimer's disease.